Imidazopyrrolidinone compounds

ABSTRACT

The invention relates to compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.

BACKGROUND OF THE INVENTION

The present invention relates to novel imidazopyrrolidinone compounds,capable of inhibiting the interaction between p53, or variants thereof,and MDM2 and/or MDM4, or variants thereof, respectively, especiallybinding to MDM2 and/or MDM4, or variants thereof, a process for thepreparation of such compounds, pharmaceutical preparations comprisingsuch compounds, uses and methods of use for such compounds in thetreatment (including therapy and/or prophylaxis), and/or related subjectmatter as specified below. p53 refers to all genes and/or proteinsencoded thereof with the names TP53, p53, TP73, p73, TP63, TP73L, p63.MDM2 refers to all genes and/or proteins encoded thereof with the namesMDM2, Mdm2, HDM2, Hdm2, MDM4 refers to all genes and/or proteins encodedthereof with the names MDM4, Mdm4, HDM4, Hdm4, MDMX, MdmX, HDMX, HdmX.

Protein p53 is known as a tumor suppressor protein which helps tocontrol cellular integrity and prevents the proliferation of permanentlydamaged cells by initiating, among other responses, growth arrest orapoptosis (controlled cell death). p53 mediates its effects in that itis a transcription factor capable of regulating a number of genes thatregulate e.g. cell cycle and apoptosis. Thus, p53 is an important cellcycle inhibitor. These activities are tightly controlled by MDM2, animportant negative regulator of the p53 tumor suppressor. “MDM2”(originally from the oncogene “murine double minute 2”) refers both tothe name of the gene as well as the protein encoded by that gene. MDM2protein functions both as an E3 ubiquitin ligase that recognizes theN-terminal trans-activation domain (TAD) of the p53 tumor suppressor andthus mediates the ubiquitin-dependent degradation of p53, and as aninhibitor of p53 transcriptional activation.

The original mouse oncogene, which codes for the MDM2 protein, wasoriginally cloned from a transformed mouse cell line. The humanhomologue of this protein was later identified and is sometimes alsocalled HDM2 (for “human double minute 2”). Further supporting the roleof MDM2 as an oncogene, several human tumor and proliferative diseasetypes have been shown to have increased levels of MDM2, including interalia soft tissue sarcomas, bone cancer, e.g. osteosarcomas, breasttumors, bladder cancer, Li-Fraumeni syndrome, brain tumor,rhabdomyosarcoma and adrenocortical carcinoma and the like. Anotherprotein belonging to the MDM2 family is MDM4, also known as MDMX.

Dysregulation of the MDM2/p53 ratio, e.g. due to mutations,polymorphisms or molecular defects in the affected cells, can thus befound in many proliferative diseases. MDM2, in view of its mentionedeffects, is capable to inhibit the activity of the tumor suppressorprotein p53, thus leading to loss of p53's tumor suppressor activity andinhibiting regulatory mechanisms that impede cells from uncontrolledproliferation. As a consequence, uncontrolled proliferation can takeplace, leading to cancers such as tumors, leukemias or otherproliferative diseases.

There is a need for new drugs that are capable of interfering with theinteraction between p53 and MDM2 or especially oncogenic variantsthereof and that thus allow p53 to exert its beneficial effect againstuncontrolled tumor growth, allowing it e.g. to accumulate, to arrest thecell cycle and/or to cause apoptosis of affected cells.

It has now been found that a novel class of imidazopyrrolidinonecompounds shows inhibition of the MDM2/p53 and/or MDM4/p53 interaction(this term including in particular Hdm2/p53 and Hdm4/p53 interaction),and in particular potent inhibition of the MDM2/p53 interaction. Inparticular, the compounds of the invention herein act as inhibitors ofMDM2 interaction with p53 by binding to MDM2, and/or act as inhibitorsof MDM4 interaction with p53 by binding to MDM4.

The corresponding compounds thus represent a novel type of compound thatare useful in the treatment of a number of disorders, such asproliferative diseases, especially cancer. The invention relatestherefore to these compounds as drugs as well as to the other inventiveembodiments indicated herein.

Particularly interesting compounds of the invention herein are highlypotent in the p53-Hdm2 inhibition (TR-FRET) Assay described herein.Compounds of particular interest possess favourable pharmacokineticproperties. They should be non-toxic and demonstrate few side-effects.Furthermore, the ideal drug candidate will exist in a physical form thatis stable, non-hygroscopic and easily formulated.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided acompound of formula (I) or a salt thereof,

wherein

A is selected from:

B is selected from:

each R¹ is independently selected from halo and methyl;

R² is selected from chloro, fluoro, trifluoromethyl, methyl and cyano;

R³ is selected from isopropyl, cyclopropyl, isobutyl, cyclobutyl andcyclopentyl, or R³ is:

wherein R²² is selected from OH, OCH₃, NH₂, NHMe, NMe₂, NHCOMe andNHCOH;

R⁴ is selected from:

wherein

R¹⁵ is independently selected from OCH₃, CH₂CH₃, OH, OCF₃ and H;

R¹⁶ is selected from H, —O—(C₁-C₄)alkyl, halo, OCF₃, CN, —C(O)NR⁹R¹⁰,—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR⁹R¹⁰,—CH₂NR⁹—C(O)R¹⁰, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR⁹R¹⁰, —CH₂C(O)OH,—C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R⁹)—C(O)—(C₁-C₄)alkyl, —NR⁹R¹⁰ and(C₁-C₄)alkyl optionally substituted by 1 or 2 OH;

R¹⁷ is selected from H, O(C₁-C₄)alkyl, —CH₂C(O)NR⁹R¹⁰,—CH₂C(O)O—(C₁-C₄)alkyl, —CH₂C(O)OH, —NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —CH₂NR⁹R¹⁰,—C(O)OCH₃ and —CH₂CN;

R¹⁸ is selected from H, O(C₁-C₄)alkyl, OH, CH₂NR⁹R¹⁰, —NR⁹R¹⁰ andazetidin-1-yl, said azetidin-1-yl being substituted with OH or both CH₃and OH,

R¹⁹ is selected from H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, —NR⁹R¹⁰,—N(R⁹)—C(O)—(C₁-C₄)alkyl and —C(O)NR⁹R¹⁰;

R²⁰ is selected from H, CH₃ and —CH₂CH₃;

R²¹ is selected from —NR⁹R¹⁰, —CH₂NR⁹R¹⁰, C(O)NR⁹R¹⁰ and CN;

R⁵ is selected from:

-   -   H,    -   heterocyclyl¹-C(O)—(CH₂)—,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH, ═O,    -   heterocyclyl¹-(C₁-C₄)alkyl-, wherein said alkyl of        heterocyclyl¹-(C₁-C₄)alkyl- is optionally substituted by 1 or 2        OH, and said heterocyclyl¹ can be optionally substituted by        methyl or ethyl,    -   (C₁-C₄)alkyl-O—C(O—(CH₂)_(m)—, and    -   cyano;

R⁶ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl-,    -   halo,    -   R⁹(R¹⁰)N—C(O)—(CH₂)_(m)—,    -   cyano,    -   R⁹(R¹⁰)N—(CH₂)_(m)—,    -   R⁹(R¹⁰)N—(CH₂)_(n)—O—(CH₂)_(m)—,    -   (C₁-C₄)alkyl-C(O)—(R¹⁰)N—(CH₂)_(m)—,    -   —O—(CH₂)_(p)-heteroaryl²;

R⁷ is selected from:

-   -   H,    -   halo, and    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy;

each R⁸ is independently selected from H, methyl, ethyl, hydroxyethyland methoxyethyl-, wherein said methyl or ethyl is optionallysubstituted with 1, 2 or 3 fluoro substituents;

each R⁹ is independently selected from H, methyl or ethyl;

each R¹⁰ is independently selected from H and (C₁-C₄) alkyl wherein said(C₁-C₄) alkyl is optionally substituted by 1 or 2 substituentsindependently selected from methoxy, ethoxy, hydroxy and halo;

R⁹ and R¹⁰, together with the N atom to which they are attached, canjoin to form a saturated 5 or 6 membered heterocyclic ring furthercomprising ring carbon atoms and optionally one ring heteroatomindependently selected from N, O and S, and wherein when the ringcontains a S atom, said S is optionally substituted with one or two oxosubstituents;

R¹¹ is H, (C₁-C₄)alkyl, (C₁-C₄) alkoxy or halo;

R¹² is H or halo;

R¹³ is selected from NH₂, —C(O)OH, —NH(C(O)—CH₃) and —C(O)—NH(CH₃);

R¹⁴ is selected from —C(O)—NR⁹(R¹⁰), (C₁-C₄)alkyl, —C(O)(C₁-C₄)alkyl,—C(O)O(C₁-C₄)alkyl;

each R²³ is independently selected from H, halo, cyclopropyl and(C₁-C₄)alkyl;

n is 1, 2 or 3;

p is 0, 1, 2 or 3;

heterocyclyl¹ is a 3, 4, 5 or 6 membered fully saturated or partiallyunsaturated monocyclic group comprising ring carbon atoms and 1 or 2ring heteroatoms independently selected from N, O and S;

heteroaryl² is 5 or 6 membered fully unsaturated monocyclic groupcomprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatomsindependently selected from N, O and S, wherein the total number of ringS atoms does not exceed 1, and the total number of ring O atoms does notexceed 1;

and

m is 0, 1 or 2.

* indicates the point of attachment to the remainder of the molecule.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 discloses the X-ray powder diffraction data for the solid formobtained from Example 79 using method A herein.

FIG. 2 discloses the X-ray powder diffraction data for the solid formobtained from Example 199 using method B herein.

FIG. 3 discloses the X-ray powder diffraction data for the solid formobtained from Example 102 using method C herein.

FIG. 4 discloses the X-ray powder diffraction data for the solid formobtained from Example 102 using method D herein.

FIG. 5 discloses the X-ray powder diffraction data for the solid formobtained from Example 102 using method E herein.

FIG. 6 discloses the X-ray powder diffraction data for the solid formobtained from Example 160 using method F herein.

FIG. 7 discloses the X-ray powder diffraction data for the solid formobtained from Example 317 using method G herein.

DETAILED DESCRIPTION OF THE INVENTION

Unless specified otherwise, the terms “compounds of the presentinvention” or a “compound of formula (I)” refer to compounds of formula(I) and subformulae thereof, salts thereof, hydrates or solvates of thecompounds or salts, as well as all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically labeledcompounds (including deuterium substitutions), as well as inherentlyformed moieties (e.g., polymorphs, solvates and/or hydrates).

For example, a “compound of the present invention” or a “compound offormula (I)” can exist in tautomeric forms when R⁸ is H. Where anembodiment is directed to one tautomer, the embodiment includes allpossible tautomeric forms.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments. Forpurposes of interpreting this specification, terms used in the singularwill also include the plural and vice versa.

In another embodiment of the invention there is provided a compound offormula (I) or salt thereof, wherein A is selected from

B is selected from

each R¹ is independently selected from halo and methyl;

R² is selected from chloro, fluoro, trifluoromethyl, methyl and cyano;

R³ is selected from isopropyl, cyclopropyl, isobutyl, cyclobutyl andcyclopentyl, or R³ is:

wherein R²² is selected from OH, OCH₃, NH₂, NHMe, NMe₂, NHCOMe andNHCOH; R⁴ is selected from:

wherein

R¹⁵ is independently selected from OCH₃, CH₂CH₃, OH, OCF₃ and H;

R¹⁶ is selected from H, —O—(C₁-C₄)alkyl, halo, OCF₃, CN, —C(O)NR⁹R¹⁰,—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR⁹R¹⁰,—CH₂NR⁹—C(O)R¹⁰, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR⁹R¹⁰, —CH₂C(O)OH,—C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R⁹)—C(O)—(C₁-C₄)alkyl, —NR⁹R¹⁰ and(C₁-C₄)alkyl optionally substituted by 1 or 2 OH;

R¹⁷ is selected from H, O(C₁-C₄)alkyl, —CH₂C(O)NR⁹R¹⁰,—CH₂C(O)O—(C₁-C₄)alkyl, —CH₂C(O)OH, —NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —CH₂NR⁹R¹⁰,—C(O)OCH₃ and —CH₂CN;

R¹⁸ is selected from H, O(C₁-C₄)alkyl, CH₂NR⁹R¹⁰, —NR⁹R¹⁰ andazetidin-1-yl, said azetidin-1-yl being substituted with OH or both CH₃and OH;

R¹⁹ is selected from H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, —NR⁹R¹⁰,—N(R⁹)—C(O)—(C₁-C₄)alkyl and —C(O)NR⁹R¹⁰;

R²⁰ is selected from H, CH₃ and —CH₂CH₃;

R²¹ is selected from —NR⁹R¹⁰, —CH₂NR⁹R¹⁰, C(O)NR⁹R¹⁰ and CN;

R⁵ is selected from:

-   -   H,    -   heterocyclyl¹-C(O)—(CH₂)—,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH, ═O,    -   heterocyclyl¹-(C₁-C₄)alkyl-, wherein said alkyl of        heterocyclyl¹-(C₁-C₄)alkyl- is optionally substituted by 1 or 2        OH, and said heterocyclyl¹ can be optionally substituted by        methyl or ethyl,    -   C₁-C₄)alkyl-O—C(O—(CH₂)_(m)—, and    -   cyano;

R⁶ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl-,    -   halo,    -   R⁹(R¹⁰)N—C(O)—(CH₂)_(m)—,    -   cyano,    -   R⁹(R¹⁰)N—(CH₂)_(m)—,    -   R⁹(R¹⁰)N—(CH₂)_(n)—O—(CH₂)_(m)—,    -   (C₁-C₄)alkyl-C(O)—(R¹⁰)N—(CH₂)_(m)—,    -   —O—(CH₂)_(p)-heteroaryl²;

R⁷ is selected from:

-   -   H,    -   halo, and    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy;

each R⁸ is independently selected from H, methyl, ethyl, hydroxyethyland methoxyethyl-;

each R⁹ is independently selected from H, methyl or ethyl;

each R¹⁰ is independently selected from H and (C₁-C₄) alkyl wherein said(C₁-C₄) alkyl is optionally substituted by 1 or 2 substituentsindependently selected from methoxy, ethoxy, hydroxy and halo;

or R⁹ and R¹⁰, together with the N atom to which they are attached, canjoin to form a saturated 5 or 6 membered heterocyclic ring furthercomprising ring carbon atoms and optionally one ring heteroatomindependently selected from N, O and S;

R¹¹ is H, (C₁-C₄)alkyl, (C₁-C₄) alkoxy or halo;

R¹² is H or halo;

R¹³ is selected from NH₂, —C(O)OH, —NH(C(O)—CH₃) and —C(O)—NH(CH₃);

R¹⁴ is selected from —C(O)—NR⁹(R¹⁰), (C₁-C₄)alkyl, —C(O)(C₁-C₄)alkyl,—C(O)O(C₁-C₄)alkyl;

each R³ is independently selected from H, halo and (C₁-C₄)alkyl;

n is 1, 2 or 3;

p is 0, 1, 2 or 3;

heterocyclyl¹ is a 3, 4, 5 or 6 membered fully saturated or partiallyunsaturated monocyclic group comprising ring carbon atoms and 1 or 2ring heteroatoms independently selected from N, O and S;

heteroaryl² is 5 or 6 membered fully unsaturated monocyclic groupcomprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatomsindependently selected from N, O and S, wherein the total number of ringS atoms does not exceed 1, and the total number of ring O atoms does notexceed 1;

m is 0, 1 or 2; and

* indicates the point of attachment to the remainder of the molecule.

In another embodiment, A is selected from:

In a further embodiment, A is selected from:

In a still further embodiment, A is selected from:

In another embodiment, when A is

the stereochemistry is:

In another embodiment, B is selected from

In a further embodiment, B is selected from:

In a still further embodiment, B is selected from:

In another embodiment, each R¹ is independently selected from chloro,fluoro and methyl.

In another embodiment, R² is selected from chloro and cyano.

In another embodiment, R³ is selected from isopropyl, cyclobutyl,cyclopropyl, 2-methoxy-1-methyl-ethyl and 2-hydroxy-1-methyl-ethyl.

In another embodiment R³ is selected from isopropyl and

In a particular embodiment, when R³ is

the stereochemistry is

In another particular embodiment, when R³ is

the stereochemistry is

In a still further embodiment, R³ is isopropyl or 1-methoxypropan-2-yl,in particular isopropyl.

In another embodiment R⁴ is selected from

In a further embodiment, R⁴ is selected from

In a further embodiment, R⁴ is selected from:

In a still further embodiment, R⁴ is selected from

in particular

As discussed herein, the terms “compounds of the present invention” or a“compound of formula (I)” include isotopically labeled compounds, suchas deuterium substitutions. As such the invention includes a compound offormula (I) wherein R⁴ is:

In another embodiment, when R⁴ is selected from a group which is orincludes:

R¹⁶ is substituted at the following positions:

in particular

In another embodiment, when R⁴ is selected from a group which is orincludes:

R¹⁷ is substituted at the following positions:

In another embodiment, when R⁴ is selected from a group which is orincludes:

R¹⁷ is substituted at the following position:

In another embodiment, when R⁴ is selected from a group which is orincludes:

R¹⁸ is substituted at the following position:

In another embodiment, R⁵ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH, ═O,    -   (C₁-C₄)alkyl-O—C(O)—(CH₂)_(m)—, and    -   cyano.

In another embodiment R⁵ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH and ═O,        and    -   (C₁-C₄)alkyl-O—C(O)—(CH₂)_(m)—.

In a further embodiment R⁵ is selected from H, methyl and(C₁-C₂)alkyl-O—C(O)—.

In a still further embodiment R⁵ is selected from H, —C(O)—O-ethyl andmethyl.

In a particular embodiment, R⁵ is H.

In another embodiment R⁶ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl-,    -   halo,    -   R⁹(R¹⁰)N—C(O)—(CH₂)_(m)—,    -   cyano,    -   R⁹(R¹⁰)N—(CH₂)_(m)—, and    -   (C₁-C₄)alkyl-C(O)—(R¹⁰)N—(CH₂)_(m)—.

In another embodiment R⁶ is selected from:

-   -   H,    -   methyl,    -   methoxy,    -   halo,    -   R⁹(R¹⁰)N—C(O)— and    -   cyano.

In a further embodiment R⁶ is selected from:

H,

-   -   methyl,    -   methoxy    -   fluoro    -   chloro    -   cyano and    -   —C(O)NH₂.

In another embodiment R⁷ is selected from H and (C₁-C₄)alkyl-, inparticular H and methyl.

In another embodiment each R⁹ is independently selected from H, methylor ethyl;

In another embodiment each R¹⁰ is independently selected from H and(C₁-C₄) alkyl wherein said (C₁-C₄) alkyl is optionally substituted by 1or 2 substituents independently selected from methoxy, ethoxy, hydroxyand halo;

In another embodiment R¹¹ is H.

In another embodiment R¹² is H or fluoro.

In another embodiment R¹⁴ is selected from —C(O)—NH(CH₃) and —C(O)OCH₃.

In another embodiment R¹⁶ is selected from H, O(C₁-C₄)alkyl, halo, OCF₃,CN, —C(O)N(CH₃)₂, —C(O)NH(CH₃), —C(O)NH(CH₂CH₂OH), —C(O)NH[CH(CH₃)₂],—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl-, —CH₂NH₂,—CH₂NH—C(O)CH₃, CH₂OH, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NH(CH₃),—CH₂C(O)N(CH₃)₂, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)OCH₃, —C(O)NH₂,—CH₂NH—C(O)CH₂OH, —CH(OH)CH(CH₃)₂, —CH(OH)CH₃, —N(CH₃)—C(O)CH₃,—NH—C(O)CH₃, —CH₂N(CH₃)—C(O)CH₃ and NH₂.

In another embodiment R¹⁶ is selected from H, OCH₃, halo, OCF₃, CN,—C(O)N(CH₃)₂, —C(O)NH(CH₃), —C(O)NH(CH₂CH₂OH), —C(O)NH[CH(CH₃)₂],—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl-, —CH₂NH₂,—CH₂NH—C(O)CH₃, CH₂OH, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NH(CH₃),—CH₂C(O)N(CH₃)₂, CH₂C(O)OH, —C(O)OH, —CH₂C(O)OCH₃, —C(O)NH₂,—CH₂NH—C(O)CH₂OH, —CH(OH)CH(CH₃)₂ and —CH(OH)CH₃.

In another embodiment R¹⁷ is selected from H, O(C₁-C₄)alkyl, CH₂CN,—CH₂C(O)NH(CH₃), —CH₂C(O)OCH₂CH₃, —CH₂C(O)OH, NH₂, C(O)NH₂,—C(O)N(CH₃)₂, C(O)NH(CH₃), —C(O)OCH₃, and —CH₂CN.

In a further embodiment R¹⁷ is selected from H, OCH₃, CH₂CN,—CH₂C(O)NH(CH₃), —CH₂C(O)OCH₂CH₃, —CH₂C(O)OH, NH₂ and —CH₂CN.

In another embodiment R¹⁸ is selected from H, O(C₁-C₄)alkyl, —CH₂NH₂,—NH(CH₃), —N(CH₃)₂, NH₂, —NCH₃(CH₂CH₂OH), —NH(CH₂CH₂OH), azetidin-1-yl,said azetidin-1-yl being substituted with OH or both CH₃ and OH.

In a further embodiment R¹⁸ is selected from H, OCH₃, —CH₂NH₂, —NH(CH₃),—N(CH₃)₂, NH₂, —NCH₃(CH₂CH₂OH), —NH(CH₂CH₂OH), azetidin-1-yl, saidazetidin-1-yl being substituted with OH or both CH₃ and OH.

In another embodiment R¹⁹ is selected from H, OCH₃ and —C(O)N(CH₃)₂.

In another embodiment R²¹ is selected from —NCH₃(CH₂CH₂OH), C(O)NH₂, CN,N(CH₃)₂ and —C(O)N(CH₃)₂.

In another embodiment, each R²³ is independently selected from H,fluoro, methyl and ethyl.

In another embodiment, when A is:

R²³ is in particular R^(23A) and R^(23B) as shown:

wherein R^(23A) is selected from H, halo and (C₁-C₄)alkyl, and

R^(23B) is selected from H and (C₁-C₄)alkyl;

In another embodiment, the compound of formula (I) has thestereochemistry shown in formula (IA):

In another embodiment, the compound of formula (I) has thestereochemistry shown in formula (IB):

In another embodiment heterocyclyl¹ is a 5 or 6 membered fully saturatedmonocyclic group comprising ring carbon atoms and 1 or 2 ringheteroatoms independently selected from N, O and S. In particularheterocyclyl¹ is pyrrolidinyl or morpholinyl.

In another embodiment heteroaryl² is a 5 or 6 membered fully unsaturatedmonocyclic group comprising ring carbon atoms and 1, 2, 3 or 4 ring Nheteroatoms. In particular, heteroaryl² is tetrazole or imidazole.

Described below are a number of embodiments (E) of the first aspect ofthe invention, where for convenience E1 is identical thereto.

E1 A compound of formula (I) as defined above, or a salt thereof.

E2 A compound of formula (I) a salt thereof according to E1, wherein Ais selected from

B is selected from

each R¹ is independently selected from halo and methyl;

R² is selected from chloro, fluoro, trifluoromethyl, methyl and cyano;

R³ is selected from isopropyl, cyclopropyl, isobutyl, cyclobutyl andcyclopentyl, or R³ is:

wherein R²² is selected from OH, OCH₃, NH₂, NHMe, NMe₂, NHCOMe andNHCOH;

R⁴ is selected from:

wherein

R¹⁵ is independently selected from OCH₃, CH₂CH₃, OH, OCF₃ and H;

R¹⁶ is selected from H, —O—(C₁-C₄)alkyl, halo, OCF₃, CN, —C(O)NR⁹R¹⁰,—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl, —CH₂NR⁹R¹⁰,—CH₂NR⁹—C(O)R¹⁰, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NR⁹R¹⁰, —CH₂C(O)OH,—C(O)OH, —CH₂C(O)O—(C₁-C₄)alkyl, —N(R⁹)—C(O)—(C₁-C₄)alkyl, —NR⁹R¹⁰ and(C₁-C₄)alkyl optionally substituted by 1 or 2 OH;

R¹⁷ is selected from H, O(C₁-C₄)alkyl, —CH₂C(O)NR⁹R¹⁰,—CH₂C(O)O—(C₁-C₄)alkyl, —CH₂C(O)OH, —NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —CH₂NR⁹R¹⁰,—C(O)OCH₃ and —CH₂CN;

R¹⁸ is selected from H, O(C₁-C₄)alkyl, CH₂NR⁹R¹⁰, —NR⁹R¹⁰ andazetidin-1-yl, said azetidin-1-yl being substituted with OH or both CH₃and OH;

R¹⁹ is selected from H, O(C₁-C₄)alkyl, (C₁-C₄)alkyl, —NR⁹R¹⁰,—N(R⁹)—C(O)—(C₁-C₄)alkyl and —C(O)NR⁹R¹⁰;

R²⁰ is selected from H, CH₃ and —CH₂CH₃;

R²¹ is selected from —NR⁹R¹⁰, —CH₂NR⁹R¹⁰, C(O)NR⁹R¹⁰ and CN;

R⁵ is selected from:

-   -   H,    -   heterocyclyl¹-C(O)—(CH₂)—,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH, ═O,    -   heterocyclyl¹-(C₁-C₄)alkyl-, wherein said alkyl of        heterocyclyl¹-(C₁-C₄)alkyl- is optionally substituted by 1 or 2        OH, and said heterocyclyl¹ can be optionally substituted by        methyl or ethyl,    -   (C₁-C₄)alkyl-O—C(O)—(CH₂)_(m)—, and    -   cyano;

R⁶ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl-,    -   halo,    -   R⁹(R¹⁰)N—C(O)—(CH₂)_(m)—,    -   cyano,    -   R⁹(R¹⁰)N—(CH₂)_(m)—,    -   R⁹(R¹⁰)N—(CH₂)_(n)—O—(CH₂)_(m)—,    -   (C₁-C₄)alkyl-C(O)(R¹⁰)N—(CH₂)_(m)—,    -   —O—(CH₂)_(p)-heteroaryl²;

R⁷ is selected from:

-   -   H,    -   halo, and    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy;

each R⁸ is independently selected from H, methyl, ethyl, hydroxyethyland methoxyethyl-;

each R⁹ is independently selected from H, methyl or ethyl;

each R¹⁰ is independently selected from H and (C₁-C₄) alkyl wherein said(C₁-C₄) alkyl is optionally substituted by 1 or 2 substituentsindependently selected from methoxy, ethoxy, hydroxy and halo;

or R⁹ and R¹⁰, together with the N atom to which they are attached, canjoin to form a saturated 5 or 6 membered heterocyclic ring furthercomprising ring carbon atoms and optionally one ring heteroatomindependently selected from N, O and S;

R¹¹ is H, (C₁-C₄)alkyl, (C₁-C₄) alkoxy or halo;

R¹² is H or halo;

R¹³ is selected from NH₂, —C(O)OH, —NH(C(O)—CH₃) and —C(O)—NH(CH₃);

R¹⁴ is selected from —C(O)—NR⁹(R¹⁰), (C₁-C₄)alkyl, —C(O)(C₁-C₄)alkyl,—C(O)O(C₁-C₄)alkyl;

each R³ is independently selected from H, halo and (C₁-C₄)alkyl;

n is 1, 2 or 3;

p is 0, 1, 2 or 3;

heterocyclyl¹ is a 3, 4, 5 or 6 membered fully saturated or partiallyunsaturated monocyclic group comprising ring carbon atoms and 1 or 2ring heteroatoms independently selected from N, O and S;

heteroaryl² is 5 or 6 membered fully unsaturated monocyclic groupcomprising ring carbon atoms and 1, 2, 3 or 4 ring heteroatomsindependently selected from N, O and S, wherein the total number of ringS atoms does not exceed 1, and the total number of ring O atoms does notexceed 1;

m is 0, 1 or 2; and

* indicates the point of attachment to the remainder of the molecule.

E3 A compound or salt thereof according to E1 or E2 wherein A isselected from:

E4 A compound or salt thereof according to any of E1 to E3, wherein A isselected from:

E5 A compound or salt thereof according to any of E1 to E3, wherein A isselected from:

E6 A compound or salt thereof according to any of E1 to E3, wherein whenA is

the stereochemistry is:

E7 A compound or salt thereof according to any of E1 to E6, wherein B isselected from

E8 A compound or salt thereof according to any of E1 to E7, wherein B isselected from:

E9 A compound or salt thereof according to any of E1 to E8, wherein B isselected from:

E100 A compound or salt thereof according to any of E1, E2 and E7 to E9,wherein each R¹ is independently selected from chloro, fluoro andmethyl.

E11 A compound or salt thereof according to any of E1 to E6 and E10,wherein R² is selected from chloro and cyano.

E12 A compound or salt thereof according to any of E1 to E11, wherein R³is selected from isopropyl, cyclobutyl, cyclopropyl,2-methoxy-1-methyl-ethyl and 2-hydroxy-1-methyl-ethyl.

E13 A compound or salt thereof according to any of E1 to E12, wherein R³is selected from isopropyl and

E14 A compound or salt thereof according to any of E1 to E13, wherein R³is isopropyl or 1-methoxypropan-2-yl, in particular isopropyl.

E15 A compound or salt thereof according to any of E1 to E14, whereinwhen R³ is

the stereochemistry is

E16 A compound or salt thereof according to any of E1 to E14, whereinwhen R³ is

the stereochemistry is

E17 A compound or salt thereof according to any of E1 to E14, wherein R³is isopropyl.

E18 A compound or salt thereof according to any of E1 to E17, wherein R⁴is selected from

E19 A compound or salt thereof according to any of E1 to E18, wherein R⁴is selected from

E20 A compound or salt thereof according to any of E1 to E19, wherein R⁴is selected from:

E21 A compound or salt thereof according to any of E1 to E20, wherein R⁴is selected from

in particular

E22 A compound or salt thereof according to any of E1 to E19, whereinwhen R⁴ is selected from a group which is or includes:

R¹⁶ is substituted at the following positions:

in particular

E23 A compound or salt thereof according to any of E1 to E18, whereinwhen R⁴ is selected from a group which is or includes:

R⁷ is substituted at the following positions:

E24 A compound or salt thereof according to any of E1 to E18, whereinwhen R⁴ is selected from a group which is or includes:

R¹⁷ is substituted at the following position:

E25 A compound or salt thereof according to any of E1 to E19, whereinwhen R⁴ is selected from a group which is or includes:

R¹⁸ is substituted at the following position

E26 A compound or salt thereof according to any of E1 to E25, wherein R⁵is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH, ═O,    -   (C₁-C₄)alkyl-O—C(O)—(CH₂)_(m)—, and    -   cyano.

E27 A compound or salt thereof according to any of E1 to E26, wherein R⁵is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, said (C₁-C₄)alkyl- being optionally substituted        with 1 or 2 substituents independently selected from OH and ═O,        and    -   (C₁-C₄)alkyl-O—C(O)—(CH₂)_(m)—.

E28 A compound or salt thereof according to any of E1 to E27, wherein R⁵is selected from H, methyl and (C₁-C₂)alkyl-O—C(O)—.

E29 A compound or salt thereof according to any of E1 to E28, wherein R⁵is selected from H, —C(O)—O-ethyl and methyl.

E30 A compound or salt thereof according to any of E1 to E29, wherein R⁵is H.

E31 A compound or salt thereof according to any of E1, E2 and E7 to E30,wherein R⁶ is selected from:

-   -   H,    -   (C₁-C₄)alkyl-, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy, optionally substituted with (C₁-C₄)alkoxy,    -   (C₁-C₄)alkoxy(C₁-C₄)alkoxy(C₁-C₄)alkyl-,    -   halo,    -   R⁹(R¹⁰)N—C(O)—(CH₂)_(m)—,    -   cyano,    -   R⁹(R¹⁰)N—(CH₂)_(m)—, and    -   (C₁-C₄)alkyl-C(O)—(R¹⁰)N—(CH₂)_(m)—.

E32: A compound or salt thereof according to any of E1, E2, and E7 toE31, wherein R⁶ is selected from:

-   -   H,    -   methyl,    -   methoxy,    -   halo,    -   R⁹(R¹⁰)N—C(O)— and    -   cyano.

E33 A compound or salt thereof according to any of E1, E2, and E7 toE32, wherein R⁶ is selected from:

-   -   H,    -   methyl,    -   methoxy    -   fluoro    -   chloro    -   cyano and    -   —C(O)NH₂.

E34 A compound or salt thereof according to any of E1 to E6 and E10 toE33 wherein R⁷ is selected from H and (C₁-C₄)alkyl-, in particular H andmethyl.

E35 A compound or salt thereof according to any of E1 to E34, whereineach R⁹ is independently selected from H, methyl and ethyl;

E36 A compound or salt thereof according to any of E1 to E34, whereineach R¹⁰ is independently selected from H and (C₁-C₄) alkyl, whereinsaid (C₁-C₄) alkyl is optionally substituted by 1 or 2 substituentsindependently selected from methoxy, ethoxy, hydroxy and halo.

E37 A compound or salt thereof according to any of E1, E2, and E6 toE36, wherein R¹¹ is H.

E38 A compound or salt thereof according to any of E1, E2, and E6 toE36, wherein R¹² is H or fluoro.

E39 A compound or salt thereof according to any of E1, E2, E7 to E9, E11to E30 and E34 to 37, wherein R¹⁴ is selected from —C(O)—NH(CH₃) and—C(O)OCH₃.

E40 A compound or salt thereof according to any of E1 to E20, E22 andE26 to E39, wherein R¹⁶ is selected from H, O(C₁-C₄)alkyl, halo, OCF₃,CN, —C(O)N(CH₃)₂, —C(O)NH(CH₃), —C(O)NH(CH₂CH₂OH), —C(O)NH[CH(CH₃)₂],—C(O)-morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl-, —CH₂NH₂,—CH₂NH—C(O)CH₃, CH₂OH, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NH(CH₃),—CH₂C(O)N(CH₃)₂, —CH₂C(O)OH, —C(O)OH, —CH₂C(O)OCH₃, —C(O)NH₂,—CH₂NH—C(O)CH₂OH, —CH(OH)CH(CH₃)₂, —CH(OH)CH₃, —N(CH₃)—C(O)CH₃,—NH—C(O)CH₃, —CH₂N(CH₃)—C(O)CH₃ and NH₂.

E41 A compound or salt thereof according any of E1 to E20, E22 and E26to E40, wherein R¹⁶ is selected from H, OCH₃, halo, OCF₃, CN,—C(O)N(CH₃)₂, —C(O)NH(CH₃), —C(O)NH(CH₂CH₂OH), —C(O)NH[CH(CH₃)₂],—C(O)morpholinyl-4-yl, hydroxy-azetidin-1-yl-carbonyl-, —CH₂NH₂,—CH₂NH—C(O)CH₃, CH₂OH, CH₂CN, methyl-imidazolyl-, —CH₂C(O)NH(CH₃),—CH₂C(O)N(CH₃)₂, CH₂C(O)OH, —C(O)OH, —CH₂C(O)OCH₃, —C(O)NH₂,—CH₂NH—C(O)CH₂OH, —CH(OH)CH(CH₃)₂ and —CH(OH)CH₃.

E42 A compound or salt thereof according to any of E1 to E18, E23, E24and E26 to E39, wherein R¹⁷ is selected from H, O(C₁-C₄)alkyl, CH₂CN,—CH₂C(O)NH(CH₃), —CH₂C(O)OCH₂CH₃, —CH₂C(O)OH, NH₂, C(O)NH₂,—C(O)N(CH₃)₂, C(O)NH(CH₃), —C(O)OCH₃, and —CH₂CN.

E43 A compound or salt thereof according to any of E1 to E18, E23, E24,E26 to E39 and E42, wherein R¹¹ is selected from H, OCH₃, CH₂CN,—CH₂C(O)NH(CH₃), —CH₂C(O)OCH₂CH₃, —CH₂C(O)OH, NH₂ and —CH₂CN.

E44 A compound or salt thereof according to any of E1 to E20, and E25 toE39, wherein R¹⁸ is selected from H, O(C₁-C₄)alkyl, —CH₂NH₂, —NH(CH₃),—N(CH₃)₂, NH₂, —NCH₃(CH₂CH₂OH), —NH(CH₂CH₂OH), azetidin-1-yl, saidazetidin-1-yl being substituted with OH or both CH₃ and OH.

E45 A compound or salt thereof according to any of E1 to E20, E25 to E39and E44, wherein R¹⁸ is selected from H, OCH₃, —CH₂NH₂, —NH(CH₃),—N(CH₃)₂, NH₂, —NCH₃(CH₂CH₂OH), —NH(CH₂CH₂OH), azetidin-1-yl, saidazetidin-1-yl being substituted with OH or both CH₃ and OH.

E46 A compound or salt thereof according to any of E1 to E17 and E26 toE39, wherein R¹⁹ is selected from H, OCH₃ and —C(O)N(CH₃)₂.

E47 A compound or salt thereof according to any of E1 to E18 and E26 toE39, wherein R²¹ is selected from —NCH₃(CH₂CH₂OH), C(O)NH₂, CN, N(CH₃)₂and —C(O)N(CH₃)₂.

E48 A compound or salt thereof according to any of E1, E2, E7 to E9, E11to E30, E34 to E36, E38 and E40 to E47 wherein each R²³ is independentlyselected from H, fluoro, methyl and ethyl.

E49 A compound or salt thereof according to any of E1, E2, E7 to E9, E11to E30, E34 to E36, E38 and E40 to E48, wherein when A is:

R²³ is in particular R^(23A) and R^(23B) as shown:

wherein R^(23A) is selected from H, halo and (C₁-C₄)alkyl, and

R^(23B) is selected from H and (C₁-C₄)alkyl.

E50 A compound or salt thereof according to any of E1 to E49, whereinthe compound of formula (I) has the stereochemistry shown in formula(IA):

E51 A compound or salt thereof according to any of E1 to E49, whereinthe compound of formula (I) has the stereochemistry shown in formula(IB):

E52 A compound of formula (I) or a salt thereof,

wherein

A is selected from:

B is selected from:

R³ is isopropyl;

R⁴ is selected from

R5 is H;

and R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²⁰ and R²¹ are as described in any of E1, E2,E40 to E45 and E47.

E53 A compound of formula (I) or a salt thereof according to E52,wherein R⁴ is selected from

E54 A compound of formula (I) or a salt thereof according to E52 or E53,wherein R⁴ is selected from:

E55 A compound of formula (I) or a salt thereof according to any of E52to E54, wherein R⁴ is selected from

E56 A compound of formula (I) or a salt thereof according to any of E1to E25 and E31 to E51, wherein heterocyclyl¹ is a 5 or 6 membered fullysaturated monocyclic group comprising ring carbon atoms and 1 or 2 ringheteroatoms independently selected from N, O and S.

E57 A compound of formula (I) or a salt thereof according to any of toany of E1 to E25 and E31 to E51, E56, wherein heterocyclyl¹ ispyrrolidinyl or morpholinyl.

E58 A compound of formula (I) or a salt thereof according to any of toany of E1, E2, E7 to E30, E34 to E37, E40 to E47, E50 and E51, whereinheteroaryl² is a 5 or 6 membered fully unsaturated monocyclic groupcomprising ring carbon atoms and 1, 2, 3 or 4 ring N heteroatoms.

E59 A compound of formula (I) or a salt thereof according to any of toany of E1, E2, E7 to E30, E34 to E37, E40 to E47, E50, E51 and E58,wherein heteroaryl² is tetrazole or imidazole.

E60 A compound of formula (I) or a salt thereof, wherein

A is selected from:

B is selected from:

R³ is selected from isopropyl, cyclobutyl, cyclopropyl,2-methoxy-1-methyl-ethyl, 2-hydroxy-1-methyl-ethyl,

R⁴ is selected from:

-   -   a.

wherein R¹⁵ is methoxy, trifluoromethoxy, ethyl, hydroxy or H, and

R¹⁶ is fluoro, H, CN, dimethylaminocarbonyl, methylaminocarbonyl,aminocarbonyl, hydroxyethylaminocarbonyl, isopropylaminocarbonyl,morpholin-4-ylcarbonyl, 3-hydroxy-azetidin-1-yl-carbonyl, aminomethyl,methylcarbonylaminomethyl, hydroxymethyl, cyanomethyl,2-methylimidazol-4-yl, methylaminocarbonylmethyl-,dimethylaminocarbonylmethyl-, methoxycarbonylmethyl-,hydroxycarbonylmethyl-, hydroxycarbonyl-,hydroxymethylcarbonylaminomethyl-, 1-hydroxy-2-methyl-propyl- or1-hydroxyethyl-;

-   -   b.

wherein R¹⁵ is methoxy and R¹⁷ is H;

-   -   c.

wherein R¹⁵ is methoxy, and R¹⁷ is H, cyanomethyl ormethylaminocarbonylmethyl-;

-   -   d.

wherein R¹⁵ is methoxy or ethyl, and R¹⁷ is H, methoxy, cyanomethyl orethoxycarbonylmethyl-, hydroxycarbonylmethyl- ormethylaminocarbonylmethyl-;

-   -   e.

-   -   wherein R¹⁵ is methoxy, H or OH, and R¹⁸ is methoxy, H,        methylamino-, dimethylamino-, amino; hydroxyethyl(methyl)amino-,        hydroxyethylamino-, 3-hydroxy-3-methyl-azetidin-1-yl-,        3-hydroxy-azetidin-1-yl-, OH, 1,1-dioxo-1-thiomorpholin-4-yl or        3-hydroxy-piperidin-1-yl;    -   f.

wherein R¹⁵ is methoxy, and R¹⁹ is methoxy or dimethylaminocarbonyl;

-   -   g.

wherein R¹⁵ is methoxy and R²⁰ is H;

-   -   h.

wherein R¹⁵ is methoxy, and R²⁰ is methyl or ethyl;

-   -   j.

wherein R¹⁵ is methoxy, and R²¹ is methoxy, hydroxyethyl(methyl)amino,aminocarbonyl or cyano; dimethylamino, dimethylaminocarbonyl,

-   -   k.

wherein R¹⁵ is methoxy;

and

-   -   l.

wherein R¹⁵ is methoxy, and R²⁰ is methyl;

and wherein

R⁵ is selected from H, ethoxycarbonyl and methyl.

E61 A compound of formula (I) or a salt thereof, selected from:

-   1:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-fluoro-2-methoxy-phenyl)-1-isopropyl-4-oxo-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   2:    5-(5-Chloro-2-methyl-phenyl)(4-chloro-2-methyl-phenyl)-2-(6-fluoro-2-methoxy-phenyl)-1-isopropyl-4-oxo-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   3:    5-(5-Chloro-2-methyl-phenyl)-5-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-trifluoromethoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   4:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile-   5:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   6:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(4-methoxy-pyridin-3-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   7:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   8:    5-(5-Chloro-2-methyl-phenyl)(4-chloro-2-methyl-phenyl)-2-(2-methoxy-pyridin-3-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   9:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl    benzamide-   10:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N-methyl    benzamide-   11:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxyethyl)-4-methoxy-benzamide-   12:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide-   13:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   14:    5-(5-Chloro-2-methyl-phenyl)(4-chloro-2-methyl-phenyl)-2-[5-(3-hydroxy-azetidine-1-carbonyl)-2-methoxy-phenyl]1H-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   15:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(3-methoxy-pyridin-4-yl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   16: 2-(5-Amino    methyl-2-methoxy-phenyl-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   17:    N-{3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzyl}-acetamide-   18:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   19:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   20:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   21:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(4-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   22:    5-(5-Chloro-2-methyl-phenyl)(4-chloro-2-methyl-phenyl)-2-(4-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   23:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl    benzamide-   24:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile-   25:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   26:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzonitrile-   27:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,6-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   28:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(3,6-pyridazin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   29:    5-(5-Chloro-2-methyl-phenyl)(4-chloro-2-methyl-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   30:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(4-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   31:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   32:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   33:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   34:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-ethyl-benzonitrile-   35:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   36:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   37:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   38:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-4-methoxy-pyrimidin-5-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   39:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(2-hydroxy-ethyl    amino)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   40:    4-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   41:    4-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   42:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   43:    4-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   44:    4-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   45:    4-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   46:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   47:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-ethyl-6-methoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   48:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   49:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-ethyl-benzonitrile-   50:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   51:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-4-methoxy-pyrimidin-5-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   52:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(2-hydroxy-ethyl    amino)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   53:    4-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   54:    4-[5-(3-Chloro-2-fluoro-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   55:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   56:    4-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   57:    4-[5-(3-Chloro-4-fluoro-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   58:    4-[5-(3-Chloro-4-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   59:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-3-methyl-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   60:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(3-hydroxy-3-methyl-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   61:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   62:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   63: 2-(4-Amino    methyl-2-methoxy-phenyl-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   64:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   65:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   66:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   67:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   68:    3-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   69:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   70:    3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl    benzamide-   71:    6-(4-Chloro-2-methyl-phenyl)-5-(4-chloro-pyrimidin-2-yl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   72:    6-(4-Chloro-phenyl)-5-(5-chloro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   73:    3-[5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl    benzamide-   74:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl    benzamide-   75:    (S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   76:    (R)(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   77:    4-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   78: 4-[5-(5-Chloro-2-methyl-phenyl)-2-(2-hydroxy-phenyl)-3    isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   79:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   80:    4-[5-(3-Chloro-4-fluoro-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   81:    3-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   82:    4-[5-(3-Chloro-4-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   83:    6-(4-Chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   84:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   85:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   86:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   87:    4-[5-(3-Chloro-4-fluoro-phenyl)-3-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   88:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-2-(2,4-dimethoxy    pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   89:    (S)-5-(5-Chloro-2-methyl-phenyl)-2-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   90:    (R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one-   91:    6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   92:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   93:    {4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   94:    4-[6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzamide-   95:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzamide-   96:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-2-oxo-1,2-dihydro-pyrimidin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   97:    5-(4-Amino-cyclohexyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   98:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexanecarboxylic    acid-   99:    N-{4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexyl}-acetamide-   100:    4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   101:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   102:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   103:    (R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   104:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexanecarboxylic    acid methylamide-   105:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   106:    {4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   107:    {4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   108:    {4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   109:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   110:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   111:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   112:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl}methyl-amino]-5-methoxy-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   113:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-((R)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   114:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-5-methoxy-pyrimidin-4-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   115:    5-(5-Chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-(4-methyl-cyclohexyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   116:    4-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazole-4-carboxylic    acid ethyl ester-   117:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   118:    4-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzonitrile-   119:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzonitrile-   120:    4-Chloro-2-[6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-benzonitrile-   121:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-5-methoxy-pyrimidin-4-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   122:    5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   123:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylic    acid methylamide-   124:    4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   125:    4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylic    acid methyl ester-   126:    2-{4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-N-methyl-acetamide-   127:    5-(5-Chloro-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   128:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   129:    6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   130:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(5-cyanomethyl-2-methoxy-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   131:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(5-cyanomethyl-2-methoxy-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   132:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(5-cyanomethyl-2-methoxy-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   133:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetonitrile-   134:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   135:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   136:    {4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   137:    {5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid ethyl ester-   138:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid-   139:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carboxylic    acid amide-   140:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid-   141:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid-   142:    4-[(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   143:    4-[(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   144:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[3-(2-methyl-3H-imidazol-4-yl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   145:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   146:    {5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid-   147:    2-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl)-N-methyl-acetamide-   148:    2-{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-N-methyl-acetamide-   149:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((S)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   150:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid ethyl ester-   151:    2-{5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-N-methyl-acetamide-   152:    {5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetic    acid ethyl ester-   153:    6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-methyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   154:    2-{-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N-methyl-acetamide-   155:    2-{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N,N-dimethyl-acetamide-   156:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((S)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   157:    2-{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N-methyl-acetamide-   158:    5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   159:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   160:    4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   161:    4-[(R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   162:    {3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-acetic    acid-   163:    (R)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   164:    (S)-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   165:    {3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-acetic    acid methyl ester-   166:    4-[(R)-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   167:    4-[5-(3-Chloro-4-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   168:    (R)-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   169:    (S)-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   170:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carbonitrile-   171:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-5-methoxy-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   172:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-5-methoxy-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   173:    3-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide-   174:    3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide-   175:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide-   176:    3-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide-   177:    5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   178:    5-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione-   179:    5-[6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione-   180:    5-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione-   181:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   182:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile-   183:    4-[5-(3-Chloro-2-fluoro-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile-   184:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   185:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   186:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   187:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(1-ethyl-5-methoxy-2-oxo-1,2-dihydro-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   188:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile-   189:    3-[(R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   190:    3-[(S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   191:    4-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile-   192:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   193:    2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   194:    3-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile-   195:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   196:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   197:    3-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   198:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   199:    4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   200:    3-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   201:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   202:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   203:    (S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   204:    (R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   205:    (S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   206:    (R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   207:    3-[6-(4-Chloro-phenyl)-5-(5-chloro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   208:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   209:    3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide-   210:    5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   211:    3-[5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile-   212:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzoic    acid-   213:    6-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   214:    6-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   215:    3-[6-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile-   216:    4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzonitrile-   217:    3-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-4-methoxy-benzamide-   218:    3-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-4-methoxy-benzamide-   219:    4-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-3-methoxy-benzamide-   220:    4-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-3-methoxy-benzamide-   221:    5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-ethyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   222:    3-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   223:    3-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide-   224:    6-(4-Chloro-2-methyl-phenyl)-5-(4-chloro-pyridin-2-yl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   225:    3-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide-   226:    3-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide-   227:    6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   228:    N-{3-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzyl}-2-hydroxy-acetamide-   229:    5-[5-Chloro-1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   230:    5-[5-Chloro-1-(2-methoxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   231:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   232:    5-(5-Chloro-1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   233:    2-(2-Amino-pyridin-4-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   234:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-[5-(1-hydroxy-2-methyl-propyl)-2-methoxy-phenyl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   235:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-[5-(1-hydroxy-ethyl)-2-methoxy-phenyl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   236:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   237:    5-(3-chloro-2-fluorophenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxy-N,N-dimethylpyridazine-3-carboxamide-   238:    2-(4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-2-methylphenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-methoxypyridin-2-yl)acetonitrile-   239:    4-(5-(3-chloro-2-fluorophenyl)-2-(2-(cyanomethyl)-5-methoxypyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-4-yl)-3-methylbenzonitrile-   240:    4-(5-(3-chloro-4-fluorophenyl)-2-(2-(cyanomethyl)-5-methoxypyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-4-yl)benzonitrile-   241:    {4-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   242:    4-[5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile-   243:    6-(4-Chloro-phenyl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   244:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(3-methoxy-1-methyl-6-oxo-1,6-dihydro-pyridazin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   245:    5-(5-Chloro-2-methyl-phenyl)-6-(5-chloro-pyridin-2-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   246:    4-[5-(3-Chloro-2-fluoro-phenyl)isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   247:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   248:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   249:    4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carboxylic    acid dimethylamide-   250:    {4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   251:    {4-[(R)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile-   252:    4-[(S)-5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   253:    4-[(R)-5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   254:    4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   255:    4-[(R)-5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   256:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-((R)-2-methoxy-1-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   257:    4-[5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-((R)-2-methoxy-1-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[34-d]imidazol-4-yl]-benzonitrile-   258:    5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   259:    5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   260:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(4-fluoro-3-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   261:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-(2-methoxy-5-methyl-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   262:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   263:    (S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   264:    (R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   265:    (S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   266:    (R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   267:    6-(4-Chloro-phenyl)-5-(4-fluoro-3-methyl-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one,    and-   268:    6-(4-Chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5-(2-methoxy-5-methyl-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one.-   269:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   270:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-pyridine-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   271:    6-(4-Chloro-2-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   272:    6-(4-Chloro-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   273:    6-(4-Chloro-2-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   274:    6-(4-Chloro-2-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   275:    5-(5-Chloro-2-methyl-phenyl)-(5-chloro-pyridin-2-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   276:    5-(5-Chloro-2-methyl-phenyl)-6-(5-chloro-pyridin-2-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   277:    4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluorobenzonitrile-   278:    4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   279:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dihydroxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   280:    (R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   281:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   282:    (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   283:    (R)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   284:    6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   285:    6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   286:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-methyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   287:    6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   288:    4-[(R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile-   289:    4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-1-yl]-2-fluoro-benzonitrile-   290:    6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   291:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,4-dimethyl-6-oxo-1,6-dihydro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   292:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   293:    6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   294:    5-(5-Chloro-1-difluoromethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   295:    5-(5-Chloro-1-methyl-d3-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   296:    5-(5-Chloro-1-ethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   297:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   298:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-oxo-1,2-dihydro-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   299:    6-(4-Chloro-phenyl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   300:    6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-(3-methoxy-6-methyl-pyridazin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   301:    5-(5-Chloro-2-methoxy-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   302:    6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5-(3-methoxy-6-methyl-pyridazin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   303:    6-(4-Chloro-2-fluoro-phenyl)-5-(3-chloro-2-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   304:    6-(4-Chloro-2-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   305:    6-(4-Chloro-2-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   306:    6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(4-fluoro-2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   307:    (S)-5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   308:    (R)-5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   309:    6-(4-Chloro-phenyl)-5-(5-cyclopropyl-4-fluoro-2-methyl-2H-pyrazol-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   310:    6-(4-Chloro-phenyl)-5-(5-cyclopropyl-4-fluoro-2-methyl-2H-pyrazol-3-yl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   311:    4-{5-(3-Chloro-2-fluoro-phenyl)-2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methoxy-pyrimidin-5-yl]-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl}-benzonitrile-   312:    4-(3-Chloro-2-fluoro-phenyl)-2-[2-((S)-3-hydroxy-piperidin-1-yl)-4-methoxy-pyrimidin-5-yl]-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl)-benzonitrile-   313:    2-(2-amino-4-methoxypyrimidin-5-yl)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   314:    2-(2-amino-4-methoxypyrimidin-5-yl)-5-(5-chloro-2-methylphenyl)-6-(4-chlorophenyl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   315:    (R)-5-(3-chloro-2-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-hydroxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   316:    (S)-(3-chloro-2-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-hydroxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   317:    (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   318:    (R)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   319:    5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   320:    5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   321:    5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   322:    (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   323:    (S)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   324:    (R)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one-   325:    (S)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one    and 326:    (R)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2-(dimethylamino)-4-methoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one.

E62: A compound of formula (I) or a salt thereof, selected from:

-   66:    5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   75:    (S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   79:    4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   101:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   102:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   122:    5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   160:    4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   164:    (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   199:    4-[(S)-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   205:    (S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   281:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   282:    (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   286:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-methyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   289:    4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,56-tetrahydro-pyrrolo[3,4-d]imidazo-4-yl]-2-fluoro-benzonitrile-   295:    5-(5-Chloro-1-methyl-d3-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   296:    5-(5-Chloro-1-ethyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   297:    5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   304:    6-(4-Chloro-2-fluoro-phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   317:    (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one    and-   322:    (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one.

E63: A compound of formula (I) or a salt thereof, selected from:

-   102:    (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   199:    4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   282:    (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   317:    (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one    and-   322:    (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one.

In the above definitions, halo means fluoro, chloro or bromo,particularly fluoro or chloro.

Alkyl, and alkoxy groups, containing the requisite number of carbonatoms, can be unbranched or branched. Examples of alkyl include, but arenot limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

‘═O’ means an oxo substituent.

Specific preferred compounds according to the invention are those listedin the Examples section below.

Where there is more than one R group of the same type in the compound offormula (I), each may be selected independently of the other; they neednot be the same group or atom.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom. Theterm “chiral” refers to molecules which have the property ofnon-superimposability on their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R—Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certaincompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible isomers, including racemic mixtures,diastereomeric mixtures and optically pure forms. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

p53 refers to the human protein itself as described by Matlashewski etal. in EMBO J. 3, 3257-62 (1984) or related family members (e.g. p73 asdescribed in Kaghad et al. in Cell 90, 809-19 (1997) and p63 asdescribed in Yang et al in Mol Cell 2, 305-16 (1998)) (named also p53wild type herein) or to any variant thereof (e.g. a splice variant,mutant, fragment or isoform due to deletion, insertion and/or exchangeof one or more, e.g. one to 200, of the amino acids) that is stillcapable to retain preferably at least 1%, more preferably at least 5%,yet more preferably at least 10%, 20%, 30%, 40%, 50% or more than 50% ofthe p53 activity in growth suppression, e.g. in the growth suppressionassay described in Pietenpol et al., Proc. Nat. Acad. Sci. USA 91,1998-2002 (1994) and, if compared with the corresponding sequence of p53wild type, shows at least 20%, more preferably at least 25% identitywith the full sequence, e.g. at least 90% identity with a partialsequence thereof. Where not mentioned otherwise, p53 generally relatesto TP53, p53, TP73, p73, TP63, TP73L, p63, or variants thereof,respectively, as just defined.

As already indicated above, MDM2 (especially when mentioned as MDM2 orvariants thereof) generally refers to all genes and/or proteins encodedthereof with the names MDM2, Mdm2, HDM2, Hdm2, or a variant thereof.MDM4 (especially when mentioned as MDM4 or variants thereof) refers toall genes and/or proteins encoded thereof with the names MDM4, Mdm4,HDM4, Hdm4, MDMX, MdmX, HDMX, HdmX, or a variant thereof.

MDM2 specifically relates to MDM2 as described in EMBO J. 10, 1565-9,Fakharzadeh et al., 1991, a variant thereof refers to a variant thereofwhich still binds to p53 in the assay system described below (e.g. asplice variant, isoform, fragment, mutant or oncogene due to deletion,insertion and/or exchange of one or more, e.g. one to 430, of the aminoacids), corresponding to the full length proteins as originallydescribed, preferably at least with 0.5%, more preferably at least with5%, 10%, 20%, 30%, 40% or especially 50% or more of the affinity of MDM2to p53, and have at least 20%, more preferably at least 25%, sequenceidentity to MDM2 or to HDM2 as originally described or as mentionedbelow specifically. Where not mentioned otherwise, MDM2 generallyrelates to MDM2, Mdm2, HDM2 or Hdm2, or variants thereof, respectively,as just defined.

MDM4 specifically relates to MDM4 as described in Genomics 43, 34-42,Shvarts et al., 1997, a variant thereof refers to a variant thereofwhich still binds to p53 in the assay system described below (e.g. asplice variant, isoform, fragment, mutant or oncogene due to deletion,insertion and/or exchange of one or more, e.g. one to 430, of the aminoacids), corresponding to the full length proteins as originallydescribed, preferably at least with 0.5%, more preferably at least with5%, 10%, 20%, 30%, 40% or especially 50% or more of the affinity of MDM4to p53, and have at least 20%, more preferably at least 25%, sequenceidentity to MDM4, to MDMX, to HDM4 or to HDM2 as originally described oras mentioned below specifically. Where not mentioned otherwise, MDM4generally relates to MDM4, Mdm4, HDM4, Hdm4, MDMX, MdmX, HDMX or HdmX,or variants thereof, respectively, as just defined.

The percentage of sequence identity, often also termed homology, betweena protein and a variant thereof is preferably determined by a computerprogram commonly employed for this purpose, such as the Gap program(Wisconsin Sequence Analysis Package, Version 8 for Unix, GeneticsComputer Group, University Research Park, Madison Wis., USA, which usesthe algorithm of Smith and Waterman (Adv. Appl. Math. 2: 482-489 (1981),especially using an affine gap search with a gap open penalty of 12 anda gap extension penalty of 1.

“Variants thereof” where mentioned means one or more variant(s).

A proto-oncogene is a normal gene that can become an oncogene, eitherafter mutation or increased expression. Proto-oncogenes code forproteins that help to regulate cell growth and differentiation.Proto-oncogenes are often involved in signal transduction and executionof mitogenic signals, usually through their protein products. Uponactivation, a proto-oncogene (or its product) becomes a tumor inducingagent, an oncogene.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by MDM2 and/or MDM4, or (ii) associated with MDM2and/or MDM4 activity, or (iii) characterized by activity (normal orabnormal) of MDM2 and/or MDM4, or (2) reducing or inhibiting theactivity of MDM2 and/or MDM4, or (3) reducing or inhibiting theexpression of MDM2 and/or MDM4. In another non-limiting embodiment, theterm “a therapeutically effective amount” refers to the amount of thecompound of the present invention that, when administered to a cell, ora tissue, or a non-cellular biological material, or a medium, iseffective to at least partially reducing or inhibiting the activity ofMDM2 and/or MDM4; or at least partially reducing or inhibiting theexpression of MDM2 and/or MDM4.

In a further embodiment, the compounds of formula (I) are particularlyuseful for the treatment of disorders of diseases associated with theactivity of MDM2.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration.

In certain embodiments, each asymmetric atom has at least 50%enantiomeric excess, at least 60% enantiomeric excess, at least 70%enantiomeric excess, at least 80% enantiomeric excess, at least 90%enantiomeric excess, at least 95% enantiomeric excess, or at least 99%enantiomeric excess in the (R)- or (S)-configuration. Substituents atatoms with unsaturated double bonds may, if possible, be present incis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water. The compoundsof the present invention, including salts, hydrates and solvatesthereof, may inherently or by design form polymorphs. Solvates orhydrates may be useful in producing crystalline forms of a compound offormula (I).

In another aspect, the present invention provides a pharmaceuticalcomposition comprising compound of formula (I) or salt thereof asdefined herein, and one or more pharmaceutically acceptable carriers. Inanother aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or salt thereof as defined herein, and one or morepharmaceutically acceptable carriers.

The pharmaceutical composition can be formulated for particular routesof administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the present invention can be made up in asolid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc. Typically, the pharmaceutical compositionsare tablets or gelatin capsules comprising the active ingredienttogether with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may bedesirable.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the present invention can beassessed by the following in vitro & in vivo methods.

The compounds of formula I in free form or in salt form exhibit valuablepharmacological properties, e.g. MDM2 and/or MDM4 modulating properties,e.g. as indicated in tests as provided in the next sections, and aretherefore indicated for therapy.

Having regard to their inhibitory effect on p53/MDM2 and/or p53/MDM4interaction, compounds of the formula (I) in free or pharmaceuticallyacceptable salt form, are useful in the treatment of conditions whichare mediated by the activity (including normal activity or especiallyoveractivity) of MDM2 and/or MDM4, or variants thereof, respectively, asdescribed, such as proliferative and/or inflammatory conditions, e.g. byactivation of the P53/MDM2 interaction, and/or that are responsive(meaning especially in a therapeutically beneficial way) to inhibitionof the p53/MDM2 interaction, most especially a disease or disorder asmentioned herein below.

Compounds of the invention are believed to be useful in the treatment ofa disease based on dysregulation of cell cycle, such as a proliferativedisorder or disease, for example cancer or tumour diseases. Inparticular, such diseases or disorders include benign or malignanttumors, a soft tissue sarcoma or a sarcoma such as liposarcoma,rhabdomyosarcoma or bone cancer, e.g. osteosarcomas, a carcinoma, suchas of the brain, kidney, liver, adrenal gland, bladder, breast, gastric,ovary, colon, rectum, prostate, pancreas, lung, vagina or thyroid, aglioblastoma, meningioma, glioma, mesothelioma, a multiple myeloma, agastrointestinal cancer, especially colon carcinoma or colorectaladenoma, a tumor of the head and neck, a melanoma, a prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, aleukemia such as acute myeloid leukemia or B-cell chronic lymphocyticleukemia, a lymphoma, such as of B- or T-cell origin, and metastases inother organs), viral infections (e.g. herpes, papilloma, HIV, Kaposi's,viral hepatitis).

Particular uses are for the treatment of benign or malignant tumors, asoft tissue sarcoma or a sarcoma such as liposarcoma, rhabdomyosarcomaor bone cancer, e.g. osteosarcomas, a carcinoma, such as of the kidney,liver, adrenal gland, bladder, breast, gastric, ovary, colon, rectum,prostate, pancreas, lung, vagina or thyroid, mesothelioma, a multiplemyeloma, a gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the head and neck, a melanoma, a prostatehyperplasia, a neoplasia, a neoplasia of epithelial character, aleukemia such as acute myeloid leukemia or B-cell chronic lymphocyticleukemia, a lymphoma, such as of B- or T-cell origin, and metastases inother organs.

Compounds of the invention are also believed to be useful in thetreatment of or a disorder or disease involving the immune system, inparticular autoimmune diseases or immune diseases resulting due totransplantation (such as rheumatoid arthritis, graft-versus-hostdisease, systemic lupus erythematosus, Sjögren's syndrome, multiplesclerosis, Hashimoto's thyreoiditis, polymyositis), chronic inflammatoryconditions, such as asthma, osteoarthritis, atherosclerosis, MorbusCrohn or inflammatory or allergic conditions of the skin, for examplepsoriasis, contact dermatitis, atopic dermatitis, alopecia greata,erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus,epidermolysis bullosa acquisita, or other inflammatory or allergicconditions of the skin or hyperproliferative disorders, (e.g.Li-Fraumeni syndrome).

In another embodiment there is provided a compound of the formula (I) orsalt thereof as defined herein, for use as a pharmaceutical.

A further embodiment provides a compound of the formula (I) or saltthereof as defined herein, for use in the treatment of a disorder or adisease mediated by the activity of MDM2 and/or MDM4.

A still further embodiment provides the use of a compound of formula (I)or salt thereof as defined herein, for the manufacture of a medicamentfor the treatment of a disorder or a disease in a subject mediated bythe activity of MDM2 and/or MDM4.

As a further embodiment, the present invention provides the use of acompound of formula (I) in therapy. In a further embodiment, the therapyis selected from a disease which may be treated by inhibition of theMDM2/p53 and/or MDM4/p53 interaction, in particular the diseases ordisorders listed herein. In one embodiment, the disease or disorder is aproliferative disease, in particular cancer. More particularly, thecancer is one of the cancer types disclosed herein.

In another embodiment, the invention provides a method of treating adisease or disorder which is treated by inhibition of the MDM2/p53and/or MDM4/p53 interaction, comprising administration of atherapeutically acceptable amount of a compound of formula (I) or saltthereof, in particular a method of treating the diseases or disorderslisted herein.

In another embodiment, the invention provides a method for the treatmentof a disorder or a disease mediated by the activity of MDM2 and/or MDM4,comprising the step of administering to a subject a therapeuticallyacceptable amount of a compound of formula (I) or salt thereof asdefined herein, in particular a method of treating the diseases ordisorders listed herein.

A further embodiment provides a method of modulating MDM2 and/or MDM4activity in a subject, comprising the step of administering to a subjecta therapeutically effective amount of a compound of formula (I) or saltthereof as defined herein.

The compounds of the formula (I) have advantageous pharmacologicalproperties and disturb the binding interaction (also referred to hereinas p53/MDM2 and p53/MDM4 interaction or as p53/MDM2 interaction solely)between p53 on the one side and MDM2 and/or MDM4 or (especiallyoncogenic) variants thereof which still are capable of binding to p53,on the other side. Disruption of the formation of the p53-MDM2 orp53-MDM4 complex is due to an inhibitor molecule binding to the p53binding site of MDM2 or MDM4.

The invention also relates to the use of a compound of the formula (I)(or a pharmaceutical formulation comprising a compound of the formula(I)) in the treatment of one or more of the diseases mentioned above andbelow where the disease(s) respond or responds (in a beneficial way,e.g. by partial or complete removal of one or more of its symptoms up tocomplete cure or remission) to an inhibition of the MDM2/p53 and/orMDM4/p53 interaction, especially where the involved MDM2 or MDM4 and/orvariant shows (e.g. in the context of other regulatory mechanisms, dueto overexpression, to mutation or the like) inadequately high or morehigher than normal activity.

The invention can also relate to the use of a compound of the formula(I) to induce cell cycle deceleration or preferably arrest and/orapoptosis in cells containing p53 or variants thereof that are stillfunctional, for sensitizing cells to one or more additionalpharmaceutically active agents, such as inducers of apoptosis and/or ofcell cycle deceleration or arrest, and to chemoprotection of normalcells through the induction of cell cycle deceleration or arrest priorto treatment with one or more other chemotherapeutic agents, to the usein rendering normal cells resistant to chemotherapeutic agents and/ortreatments, and/or the use in protecting cells from toxic side effectsof chemotherapeutic agents or treatments, such as side effects resultingin mucositis, stomatitis, xerostomia, gastrointestinal disorders and/oralopecia.

A compound of the formula (I) may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors,such as RAD001; antineoplastic antimetabolites; platin compounds;compounds targeting/decreasing a protein or lipid kinase activity andfurther anti-angiogenic compounds; compounds which target, decrease orinhibit the activity of a protein or lipid phosphatase; gonadorelinagonists; anti-androgens; methionine aminopeptidase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies, such as HCD122; heparanase inhibitors; inhibitors of Rasoncogenic isoforms; telomerase inhibitors; proteasome inhibitors;compounds used in the treatment of hematologic malignancies, such asfludarabine; compounds which target, decrease or inhibit the activity ofFlt-3, such as PKC412; Hsp900 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics andAUY922; temozolomide (TEMODAL™); kinesin spindle protein inhibitors,such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; PI3K inhibitors, such asBEZ235; RAF inhibitors, such as RAF265; MEK inhibitors such asARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer, leucovorin, EDG binders, antileukemia compounds, ribonucleotidereductase inhibitors, S-adenosylmethionine decarboxylase inhibitors,regulators of apoptosis, antiproliferative antibodies or otherchemotherapeutic compounds. Further, alternatively or in addition theymay be used in combination with other tumor treatment approaches,including surgery, ionizing radiation, photodynamic therapy, implants,e.g. with corticosteroids, hormones, or they may be used asradiosensitizers. Also, in anti-inflammatory and/or antiproliferativetreatment, combination with anti-inflammatory drugs is included.Combination is also possible with antihistamine drug substances,bronchodilatatory drugs, NSAID or antagonists of chemokine receptors.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX™), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL™.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g., in the form as it is marketed, e.g. under the trademark VINBLASTINR.P. Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; or a “protein or lipid phosphatase activity”; or “furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, e.g.,

a) compounds targeting, decreasing or inhibiting the activity of theplatelet-derived growth factor-receptors (PDGFR), such as compoundswhich target, decrease or inhibit the activity of PDGFR, especiallycompounds which inhibit the PDGF receptor, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 andGFB-111;

b) compounds targeting, decreasing or inhibiting the activity of thefibroblast growth factor-receptors (FGFR);

c) compounds targeting, decreasing or inhibiting the activity of theinsulin-like growth factor receptor I (IGF-IR), such as compounds whichtarget, decrease or inhibit the activity of IGF-IR, especially compoundswhich inhibit the kinase activity of IGF-I receptor, such as thosecompounds disclosed in WO 02/092599, or antibodies that target theextracellular domain of IGF-I receptor or its growth factors;

d) compounds targeting, decreasing or inhibiting the activity of the Trkreceptor tyrosine kinase family, or ephrin B4 inhibitors;

e) compounds targeting, decreasing or inhibiting the activity of the Axlreceptor tyrosine kinase family;

f) compounds targeting, decreasing or inhibiting the activity of the Retreceptor tyrosine kinase;

g) compounds targeting, decreasing or inhibiting the activity of theKit/SCFR receptor tyrosine kinase, i.e C-kit receptor tyrosinekinases—(part of the PDGFR family), such as compounds which target,decrease or inhibit the activity of the c-Kit receptor tyrosine kinasefamily, especially compounds which inhibit the c-Kit receptor, e.g.imatinib;

h) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, e.g. aN-phenyl-2-pyrimidine-amine derivative, e.g. imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825);

i) compounds targeting, decreasing or inhibiting the activity of membersof the protein kinase C (PKC) and Raf family of serine/threoninekinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPKfamily members, and/or members of the cyclin-dependent kinase family(CDK) and are especially those staurosporine derivatives disclosed inU.S. Pat. No. 5,093,330, e.g. midostaurin; examples of further compoundsinclude e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds such as those disclosed in WO00/09495; FTIs; BEZ235 (a PI3K inhibitor) or AT7519 (CDK inhibitor);

j) compounds targeting, decreasing or inhibiting the activity ofprotein-tyrosine kinase inhibitors, such as compounds which target,decrease or inhibit the activity of protein-tyrosine kinase inhibitorsinclude imatinib mesylate (GLEEVEC™) or tyrphostin. A tyrphostin ispreferably a low molecular weight (Mr<1500) compound, or apharmaceutically acceptable salt thereof, especially a compound selectedfrom the benzylidenemalonitrile class or the S-arylbenzenemalonirile orbisubstrate quinoline class of compounds, more especially any compoundselected from the group consisting of Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin);

k) compounds targeting, decreasing or inhibiting the activity of theepidermal growth factor family of receptor tyrosine kinases (EGFR,ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such ascompounds which target, decrease or inhibit the activity of theepidermal growth factor receptor family are especially compounds,proteins or antibodies which inhibit members of the EGF receptortyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 orbind to EGF or EGF related ligands, and are in particular thosecompounds, proteins or monoclonal antibodies generically andspecifically disclosed in WO 97/02266, e.g. the compound of ex. 39, orin EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983 and, especially, WO 96/30347 (e.g. compound knownas CP 358774), WO 96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.compound ZM105180); e.g. trastuzumab (Herceptin™), cetuximab (Erbitux™),Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5,E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidinederivatives which are disclosed in WO 03/013541, also; and

l) compounds targeting, decreasing or inhibiting the activity of thec-Met receptor, such as compounds which target, decrease or inhibit theactivity of c-Met, especially compounds which inhibit the kinaseactivity of c-Met receptor, or antibodies that target the extracellulardomain of c-Met or bind to HGF;

m) compounds targeting, decreasing or inhibiting the activity of PI3K,such as BEZ235 or BKM120;

n) compounds targeting, decreasing or inhibiting the activity of thecyclin dependent kinase family, such as PD 0332991.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (THALOMID) and TNP-470.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, e.g. okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes are e.g. retinoicacid, α- γ- or δ-tocopherol or α- γ- or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune™), everolimus (Certican™ orAfinitor™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetrazolyle derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,e.g. PKC412, TK1258, midostaurin, a staurosporine derivative, SU11248and MLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors. An example HSP90 inhibitor isAUY922.

The term “regulators of apoptosis” as used herein includes, but is notlimited to, compounds targeting, decreasing or inhibiting the activityof Bcl2 family members (such as ABT-263) and IAP family members (such asAEG40826); or inducing apoptosis by known or unknown mechanism(s) ofaction (e.g. TRAIL antibody, DR5 antibody).

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan™), PRO64553 (anti-CD40), 2C4Antibody and HCD122 antibody (anti-CD40). By antibodies is meant e.g.intact monoclonal antibodies, polyclonal antibodies, multispecificantibodies formed from at least 2 intact antibodies, and antibodiesfragments so long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of theformula (I) can be used in combination with standard leukemia therapies,especially in combination with therapies used for the treatment of AML.In particular, compounds of the formula (I) can be administered incombination with, e.g., farnesyl transferase inhibitors and/or otherdrugs useful for the treatment of AML, such as Daunorubicin, Adriamycin,Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum andPKC412.

The term “antileukemic compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2′-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopudne (6-MP) and fludarabine phosphate.

Compounds which target, decrease or inhibit activity of histonedeacetylase (HDAC) inhibitors such as sodium butyrate andsuberoylanilide hydroxamic acid (SAHA) inhibit the activity of theenzymes known as histone deacetylases. Specific HDAC inhibitors includeMS275, SAHA, FK228 (formerly FR901228), Trichostatin A, LDH589 disclosedin WO 02/22577 and compounds disclosed in U.S. Pat. No. 6,552,065, inparticular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]-methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

Somatostatin receptor antagonists as used herein refer to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230 (pasireotide).

Tumor cell damaging approaches refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720.

The term “ribonucleotide reductase inhibitors” refers to pyrimidine orpurine nucleoside analogs including, but not limited to, fludarabineand/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil,cladribine, 6-mercaptopurine (especially in combination with ara-Cagainst ALL) and/or pentostatin. Ribonucleotide reductase inhibitors areespecially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives,such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned inNandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; thoseas described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218(1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770(1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); andMordenti et al., Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al.,Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN, described by O'Reilly etal., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190;ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies oranti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g.Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™), axitinib,(N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide,also known as AG013736, and described in PCT Publication No. WO01/002369), Brivanib Alaninate((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanoate,also known as BMS-582664), motesanib(N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyrdinecarboxamide,and described in PCT Publication No. WO 02/066470), pasireotide (alsoknown as SOM230, and described in PCT Publication No. WO 02/010192),sorafenib (sold under the tradename Nexavar®).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as e.g. VISUDYNE™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone.hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such as e.g.fluocinolone, dexamethasone.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

None of the quotations of references made within the present disclosureis to be understood as an admission that the references cited are priorart that would negatively affect the patentability of the presentinvention.

The above-mentioned compounds, which can be used in combination with acompound of the formula (I), can be prepared and administered asdescribed in the art, such as in the documents cited above.

A compound of the formula (I) can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic (including prophylactic) compounds being staggered or givenindependently of one another, or the combined administration of fixedcombinations and one or more other therapeutic compounds. A compound ofthe formula (I) can besides or in addition be administered especiallyfor tumor therapy in combination with chemotherapy, radiotherapy,immunotherapy, phototherapy, surgical intervention, or a combination ofthese. Long-term therapy is equally possible as is adjuvant therapy inthe context of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

In another embodiment, the invention provides a compound of the formula(I) or salt thereof as defined herein, in combination with one or moretherapeutically active agents. In particular, the other therapeuticagent is selected from one or more of the combination partners disclosedherein.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by inhibition of the MDM2/p53 and/or MDM4/p53interaction. Products provided as a combined preparation include acomposition comprising the compound of formula (I) and the othertherapeutic agent(s) together in the same pharmaceutical composition, orthe compound of formula (I) and the other therapeutic agent(s) inseparate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or condition mediated by inhibition of theMDM2/p53 and/or MDM4/p53 interaction, wherein the medicament is preparedfor administration with another therapeutic agent. The invention alsoprovides the use of another therapeutic agent for treating a disease orcondition mediated by inhibition of the MDM2/p53 and/or MDM4/p53interaction, wherein the medicament is administered with a compound offormula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or condition mediated by inhibition of theMDM2/p53 and/or MDM4/p53 interaction, wherein the compound of formula(I) is prepared for administration with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by inhibition of the MDM2/p53and/or MDM4/p53 interaction, wherein the other therapeutic agent isprepared for administration with a compound of formula (I). Theinvention also provides a compound of formula (I) for use in a method oftreating a disease or condition mediated by inhibition of the MDM2/p53and/or MDM4/p53 interaction, wherein the compound of formula (I) isadministered with another therapeutic agent. The invention also providesanother therapeutic agent for use in a method of treating a disease orcondition mediated by inhibition of the MDM2/p53 and/or MDM4/p53interaction, wherein the other therapeutic agent is administered with acompound of formula (I). In particular the disease or condition mediatedby inhibition of the MDM2/p53 and/or MDM4/p53 interaction is aproliferative disease, preferably cancer, more preferably one of thecancer types described herein.

The invention also provides the use of a compound of formula (I) fortreating a disease or condition mediated by inhibition of the MDM2/p53and/or MDM4/p53 interaction, wherein the patient has previously (e.g.within 24 hours) been treated with another therapeutic agent. Theinvention also provides the use of another therapeutic agent fortreating a disease or condition mediated by inhibition of the MDM2/p53and/or MDM4/p53 interaction, wherein the patient has previously (e.g.within 24 hours) been treated with a compound of formula (I).

Synthetic Methods

Typically, the compounds of formula (I) can be prepared according to theSchemes, intermediate processes and examples provided infra. The skilledperson is aware that such methods can be modified using methods known inthe art. For example, chiral separation can take place earlier or laterin a route. Reagents, or quantities of them, can be exchanged oroptimized, and reactions can be modified to enable one-pot reactions.

Abbreviations

-   Ac acetyl-   AcOH acetic acid-   AlCl₃ aluminium trichloride-   aq. aqueous-   API atmospheric pressure ionization-   Boc tert-butoxycarbonyl-   brine saturated (at rt) sodium chloride solution-   bs broad singulet-   ^(n)BuOH n-butanol-   ^(t)Bu tert-butyl-   CDI carbonyl diimidazole-   Celite trademark of Celite Corp. (World Minerals Inc.), Santa    Barbara, Calif., USA, for filtering aid based on kieselguhr-   CH₃CN acetonitrile-   conc. concentrated-   d doublett-   DCM dichloromethane-   DEA diethylamine-   DIEIA N,N-diethyl-isopropylamine-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   ES-MS electrospray mass spectrometry-   Et ethyl-   Et₃N triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   equiv equivalents-   h hour(s)-   HATU    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphat-   HBr hydrogen bromide-   HCl hydrogen chloride-   HOAt 1-hydroxy-7-azabenzotriazole-   HPLC high-performance liquid chromatography-   IPAm isopropylamine-   iPr isopropyl-   K₂CO₃ potassium carbonate-   KHMDS potassium hexamethyldisilazide-   KO^(t)Bu potassium-tert-butoxylate-   KOH potassium hydroxide-   K₃PO₄ potassium phosphate-   LAH lithium aluminium hydride-   LC liquid chromatography-   LDA lithium diisopropylamide-   LiOH lithium hydroxide-   Me methyl-   MeI methyl iodide-   MeOH methanol-   MgSO₄ magnesium sulfate-   M multiplett-   min minute(s)-   mL milliliter(s)-   MS Mass Spectrometry-   MsCl methanesulfonyl chloride-   Ms₂O methanesulfonic acid anhydride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   NaOMe sodium methoxide-   NaOEt sodium ethoxide-   NaO^(t)Bu sodium tert-butoxide-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   n.d. not determined-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NIS N-iodosuccinimide-   NMM 4-N-methylmorpholine-   NMR nuclear magnetic resonance-   Ph phenyl-   POCl₃ phosphorus (III) oxychloride-   rt (or RT) room temperature-   R_(f) TLC retention factor-   s singulet-   scCO₂ super critical CO₂-   sep septet-   t triplet-   TBAF tetrabutylammonium fluoride-   TBAHS tetrabutylammonium hydrogen sulfate-   TBME tert-butylmethylether-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethylammonium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofurane-   TLC thin layer chromatography-   TMS trimethylsilyl-   TMSCl trimethylsilyl chloride-   t_(R) time of retention-   TsCl p-toluenesulfonyl chloride-   TsOH p-toluenesulfonic acid-   UV ultraviolet

1H-NMR measurements were performed on a Bruker Ultrashield™ 400 (400MHz), Bruker Ultrashield™ 600 (600 MHz) or a 500 MHz DRX BrukerCryoProbe (500 MHz) spectrometer using or not trimethylsilane as aninternal standard. Chemical shifts (d-values) are reported in ppmdownfield from tetramethylsilane, coupling constants (J) are given inHz, spectra splitting pattern are designated as singulet (s), doublet(d), doublet doublet (dd), triplet (t), quadruplet (q), multiplet ormore overlapping signals (m), broad signal (br). Solvents are given inparentheses.

TLC were performed with precoated silica gel 60 F₂₅₄ glass plates(Merck, Darmstadt, Germany) using the respective named solvent systems.Visualization was generally done by UV light (254 nm).

HPLC Conditions:

LC-MS 1:

Column: Ascentis Express C18 2.1×30 mm, 2.7 μm. Flow: 1.2 mL/min. Columntemperature: 50° C. Gradient: 2% to 98% B in 1.4 min, 98% B for 0.75min, 98% to 2% B in 0.04 min, 98% B for 0.01 min; A=water+0.05% formicacid+0.05% ammonium acetate, B=acetonitrile+0.04% formic acid

Detection full scan: 215-350 nM

LC-MS 2:

Column: Acquity HSS T3 2.1×50 mm, 1.8 μm. Flow: 1.2 mL/min. Columntemperature: 50° C. Gradient: 2% to 98% B in 1.4 min, 98% B for 0.75min, 98% to 2% B in 0.04 min, 2% B for 0.01 min; A=water+0.05% formicacid+3.75 mM ammonium acetate, B=acetonitrile+0.04% formic acid

Detection full scan: 215-350 nM

LC-MS 3:

Column: Acquity HSS T3 2.1×50 mm, 1.8 μm. Flow: 1.2 mL/min. Columntemperature: 50° C. Gradient: 2% to 98% B in 1.4 min, 98% B for 0.75min, 98% to 2% B in 0.04 min, 2% B for 0.01 min; A=water+0.05% formicacid+0.05% ammonium acetate, B=acetonitrile+0.04% formic acid

Detection full scan: 215-350 nM

LC-MS 4:

Column: Acquity HSS T3 2.1×50 mm, 1.8 μm. Flow: 1.0 mL/min. Columntemperature: 60° C. Gradient: 5% to 98% B in 1.4 min, 98% B for 0.75min, 98% to 2% B in 0.04 min, 2% B for 0.01 min; A=water+0.05% formicacid+3.75 mM ammonium acetate, B=acetonitrile+0.04% formic acid

Detection full scan: 215-350 nM

HPLC Methods:

HPLC 1:

Column: Waters Chromolith Performance RP-18e 100-4,6. Flow: 2 mL/min.Column temperature: Rt. Gradient: 2% B for 1 min, 2% to 100% B in 8 min,100% B for 2 min, A=0.1% HCOOH in water, B=acetonitrile 0.1% HCOOH

HPLC 2:

Column: Nucleosil 100-3 C18 HD, 4.0×70 mm. Flow: 1 mL/min. Columntemperature: 30° C. Gradient: 2% to 100% B in 5 min, 100% B for 1.5 min,100% to 2% B in 0.5 min; A=0.01% TFA in water, B=0.01% TFA inacetonitrile

MS Methods:

MS1:

Electrospray ionization mass spectra. Positive and negative alternating.

DAD-UV 210-400 nm.

Scan range 100-1600 Da in 0.4 seconds

Scheme 1 illustrates one representative method of preparing2-bromo-N-alkyl-1H-imidazole-4-carboxylic acid ester intermediates (e.g.intermediate A). The illustrated method follows the known literatureprocedure (Org. Lett. 2002, 4(23), 4133) for the preparation of(Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester [CAS 72130-97-3]and the subsequent cyclization reaction with primary amines to build upthe imidazole scaffold typically conducted in refluxing n-butanol. Thefollowing bromination step is typically performed at room temperatureusing N-bromosuccinimide in THF, acetonitrile, acetic acid or mixturesthereof as solvent systems.

Scheme 2 illustrates one method of preparing compounds of the invention(e.g. example 1). 2-Bromo imidazole 4-carboxylic acid ester ismetallated at low temperature (typically LDA at −70° C. to −80° C.; THF)and quenched by addition of a representative benzaldehyde. The resultingalcohol products are converted to corresponding mesylate derivatives bytreatment with mesyl anhydride in the presence of a base such astriethylamine in a solvent such as dichloromethane in a temperaturerange from 0° C. to 10° C. Mesylates are subjected in situ tonucleophilic substitution by addition of appropriate primary amines oranilines; where typically the reaction is allowed to come to completionat ambient temperature. Hydrolysis of the carboxylic ester is achievedby treatment with alkali base such as lithium or sodium hydroxide insolvent mixture of THF/methanol/water at ambient or slightly elevatedtemperature. Ring closure to build the bicyclic core is effected byintramolecular amide coupling using reagents such as HATU or TBTU in thepresence of organic base (e.g. NMM; Hünig's base) typically using DMF assolvent, or using 1-chloro-N,N,2-trimethyl-1-propenylamine in CH₂Cl₂, orPOCl₃ or POBr₃ to form the acid chloride or bromide respectively, whichcan undergo cyclisation. Final cross coupling reactions of the resulting2-bromo imidazo pyrrolidinone intermediates with aryl- orheteroarylboronic esters or -acids are conducted under Suzuki-typeconditions; utilizing catalysts such as Pd(PPh₃)₄ or Pd(dppf)Cl₂—CH₂Cl₂complex in the presence of excess of an inorganic base (e.g. K₃PO₄ orKF) in solvent systems such as dioxane/water in a temperature range from80° C. to 100° C.

Scheme 3 illustrates an alternative method of preparing compounds of theinvention (e.g. example 64) by reversal order of steps. Alcoholintermediates obtained by the same methods as described above aresubjected to palladium catalyzed cross coupling reactions with arylboronates or boronic acids. The alcohol functionality of resultingproducts is then mesylated and submitted to nucleophilic substitutionreactions with appropriate amines using similar or identical conditions(MsCl or Ms₂O) as described above. Finally the bicyclicimidazo-pyrrolidinone scaffold is built up by ester hydrolysis and againintramolecular amide coupling using HATU as coupling reagent in asolvent such as DMF at slightly elevated temperature (60-80° C.).

Scheme 4 illustrates another alternative route for the preparation ofcompounds of this invention (e.g. examples 85/86). Herewith directamidation of imidazo ester intermediates is effected by trimethylaluminium followed by construction of the 5/5 bicycle throughintramolecular substitution of the benzylic alcohol under acidicconditions (e.g. H₂SO₄). Final coupling steps with aryl boronic acid oresters are performed according to the protocols as described above.

Unless otherwise stated all reactions are performed under an inertatmosphere (argon).

Intermediate A 2-Bromo-1-isopropyl-1H-imidazole-4-carboxylic acid ethylester

NBS (38.9 g, 218 mmol) was added to a solution of1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (step A1; 30.6 g,168 mmol) in THF (500 ml) and stirred for 18 h at rt. The reactionmixture was diluted with EtOAc, washed twice with 30% aq. Na₂S₂O₃ andwater and re-extracted with EtOAc. Combined organic layers were driedand evaporated. The remaining crude product was purified by flashchromatography (silica gel, heptanes/EtOAc, 100:0→25:75). t_(R): 0.81min (LC-MS 2); ESI-MS: 261.3/263.3 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆,600 MHz) δ (ppm) 8.20 (s, 1H), 4.46 (sep, 1H), 4.23 (q, 2H), 1.42 (d,6H), 1.26 (t, 3H).

Step A1 1-Isopropyl-1H-imidazole-4-carboxylic acid ethyl ester

Propane-2-amine (161 ml, 189 mmol) was added to a solution of((Z)-2-N,N-dimethylamino-1-ethoxycarbonyl-vinyl)-methylidyne-ammonium(step A2; 32 g, 189 mmol) in n-BuOH (250 ml) and stirred for 15 h at130° C. The solvent was evaporated under reduced pressure and theremaining crude material purified by flash chromatography(heptanes/EtOAc, 100:0→20:80). ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm) 7.96(s, 1H), 7.81 (s, 1H), 4.44 (sep, 1H), 4.19 (q, 2H), 1.40 (d, 6H), 1.23(t, 3H).

Step A2 (Z)-3-Dimethylamino-2-isocyano-acrylic acid ethyl ester

To a solution of ethyl-2-isocyanate (575 g, 5083 mmol) in EtOH (6.5 L)at 0° C. was added dropwise 1,1-diethoxy-N,N-dimethanamine (1.2 L, 6608mmol). The mixture was stirred at rt for 30 h. The reaction mixture wasdiluted with TBME (1.5 L), fixed on silica gel and filtered. The motherliquor was concentrated. The residue was purified by MPLC (Column880×150 mm, 7 kg silica gel, Flow 1000 ml/min, heptane/EtOAc,85:15→0:100). t_(R): 0.74 min (LC-MS 2); ESI-MS: 169.1 [M+H]⁺ (LC-MS 2);¹H-NMR (CDCl₃, 400 MHz) δ (ppm) 7.15 (s, 2H), 4.18 (q, 2H), 3.20 (bs,6H), 1.26 (t, 3H).

Intermediate B2-Bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

LDA (63 mL, 2M solution in THF, 126 mmol) was slowly (over 30 min) addedto a solution of 2-bromo-1-isopropyl-1H-imidazole-4-carboxylic acidethyl ester (intermediate A; 11.0 g, 42.1 mmol) in THF (200 mL) at −78°C. After 2 h at −78° C., a solution of 4-chlorobenzaldehyde (8.9 g, 63.2mmol) in THF (10 mL) was slowly added and the reaction mixture wasallowed to warm to −20° C. over 30 min. The reaction mixture wasquenched at −20° C. with 6 ml of acetic acid, concentrated and taken upin EtOAc/water, extracted twice with EtOAc. The combined organicextracts were washed with water and brine, dried (Na₂SO₄) andconcentrated. The crude material was purified by chromatography(hexane/EtOAc, 60:40) to afford an orange foam. This was treated with100 ml of 10% Et₂O/hexane overnight and the resulting solid was filteredand rinsed with hexane to give the title compound as a white solid.ESI-MS: 403.1 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 0.90 (d,J=7.04 Hz, 3H) 1.26 (t, J=7.04 Hz, 3H) 1.45 (d, J=7.04 Hz, 3H) 4.25 (qd,J=7.04, 3.13 Hz, 2H) 4.69 (quin, J=7.04 Hz, 1H) 6.73 (d, J=4.30 Hz, 1H)6.83 (d, J=4.30 Hz, 1H) 7.27 (m, J=8.60 Hz, 2H) 7.41 (m, J=8.60 Hz, 2H);R_(f)=0.15 (hexane/EtOAc, 60:40)

Intermediate C2-Bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate B using 4-chloro-2-methyl benzaldehyde. ESI-MS: 417.2[M+H]⁺ (LC-MS 1); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.46 (d, 1H), 7.31 (d,1H), 7.25 (s, 1H), 6.83 (s, 1H), 6.57 (s, 1H), 4.77 (sep, 1H), 4.25 (q,2H), 2.09 (s, 3H), 1.47 (d, 3H), 1.26 (t, 3H), 1.02 (d, 3H).

Intermediate D5-[(4-Chloro-2-methyl-phenyl)hydroxymethyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

To a solution of2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate C, 3.5 g, 8.4 mmol) in dioxane (80ml)/H₂O (20 ml) were added 2-methoxy-phenyl boronic acid (2.0 g, 13.2mmol), K₂CO₃ (3 g, 21.7 mmol). The mixture was degassed for 5 min andthen Pd(PPh₃)₄ (1.7 g, 1.5 mmol) was added. The mixture was stirred at100° C. for 2 h to give a complete conversion. Dioxane was removed underreduced pressure. The residual material was dissolved in EtOAc andextracted with brine. The aqueous layer was washed with EtOAc. Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The product was fixed on silica gel and purifiedby flash chromatography (silica gel, solvent: CH₂Cl₂/EtOAc, 100:0→80:20)to give the title compound as a yellow foam. t_(R): 1.27 min (LC-MS 2);ESI-MS 433.3 [M+H]⁺ (LC-MS 2). ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.56-7.48(m, 2H), 7.29-7.05 (m, 3H), 7.34-7.29 (m, 1H), 7.10-7.96 (m, 1H),6.94-6.91 (m, 1H), 6.52 (d, 1H), 4.58-4.52 (m, 1H), 4.24 (q, 2H),3.73/3.68 (s, 3H), 2.16 (s, 3H), 1.27 (t, 3H), 1.05 (d, 3H), 0.58 (d,3H).

Intermediate E2-Bromo-5-[(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

2-Bromo-5-[(4-chloro-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid (step E1; 4.7 g, 9.4 mmol), TBTU (3.6 g, 11.3 mmol), DIEA (3.6 g,28.2 mmol) were dissolved in DMF (50 mL) and stirred at 80° C. for 7 h.The reaction mixture was diluted in EtOAc/water, extracted twice withEtOAc and the combined organic extracts were washed with water andbrine, dried (Na₂SO₄) and concentrated. The crude material was purifiedby flash chromatography (silica gel, hexanes/EtOAc, 100:0→40:60) toafford the title compound as a white solid; ESI-MS: 479.2 [M+H]⁺ (LC-MS2); ¹H-NMR (DMSO-de, 400 MHz) δ ppm 0.74 (d, J=6.65 Hz, 3H) 1.25 (d,J=6.65 Hz, 1H) 1.30-1.46 (m, 3H) 1.84 (br. s., 2H) 4.52 (dt, J=13.39,6.79 Hz, 1H) 6.55 (br. s., 1H) 7.03-7.30 (m, 4H) 7.36 (d, J=7.82 Hz, 2H)7.72 (d, J=1.56 Hz, 1H).

Step E12-Bromo-5-[4-chloro-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid

NaOH (100 mL, 2 M aqueous solution, 200 mmol) was added to a solution of2-bromo-5-[(4-chloro-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (step E2; 5.0 g, 9.6 mmol) in THF (100 mL) and MeOH(100 mL) at rt and reactants were stirred at rt for 2 h. THF and MeOHwere evaporated, then the mixture was diluted in EtOAc/H₂O and the pHwas adjusted to 5 with diluted HCl. The aqueous layer was extracted oncewith EtOAc. The organic extract was dried (Na₂SO₄) and concentrated toafford an off-white foam; ESI-MS: 598.2 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 1.20 (d, J=18.38 Hz, 3H) 1.44 (d, J=6.65 Hz,3H) 2.16 (s, 3H) 4.97 (d, J=7.04 Hz, 1H) 6.62 (dd, J=7.82, 1.95 Hz, 2H)6.78 (d, J=2.35 Hz, 1H) 7.03 (d, J=7.82 Hz, 1H) 7.27 (m, 2H) 7.42 (m,J=8.60 Hz, 2H).

Step E22-Bromo-5-[(4-chloro-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

Ms₂O (3.6 g, 20.9 mmol) was added to a stirred solution of2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B; 4.2 g, 20.9 mmol) and TEA (5.3 g, 52.0mmol) in DCM (80 mL) at 5° C. and the reaction mixture was stirred at 5°C. for 15 min. 5-Chloro-2-methyl aniline (2.2 g, 15.7 mmol) was thenadded. The reaction mixture was allowed to reach rt in 45 min andstirred at rt for 2 h. The reaction mixture was diluted in DCM/water,extracted twice with DCM and the combined organic extracts were washedwith brine, dried (Na₂SO₄) and concentrated. The crude was purified byflash chromatography (silica gel, EtOAc/hexanes 2:8) to afford the titlecompound as a white foam; ESI-MS: 526.2 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d, 400 MHz) δ ppm 1.15 (dd, J=9.97, 4.11 Hz, 2H) 1.15 (s, 1H) 1.24(t, J=7.23 Hz, 3H) 1.45 (d, J=7.04 Hz, 3H) 2.17 (s, 3H) 4.24 (quin,J=6.74 Hz, 2H) 4.83-5.04 (m, 1H) 5.92 (d, J=5.47 Hz, 1H) 6.47 (bs, 1H)6.63 (dd, J=7.82, 1.95 Hz, 1H) 6.79 (bs, 1H) 7.04 (d, J=8.21 Hz, 1H)7.26 (m, J=8.60 Hz, 2H) 7.43 (m, J=8.60 Hz, 2H).

Intermediate F2-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The product from step F1 (4.6 g, 7.1 mmol) was dissolved in DMF (100 mL)and NMM (2.2 g, 2.3 mL, 21.3 mmol) and HATU (2.8 g, 7.5 mmol) were addedand the reaction mixture stirred at rt for 18 h. After completion thetemperature was raised to 80° C. and stirring continued for 3 h. DMF wasremoved under reduced pressure and the residual material dissolved inEtOAc. The organic solution was washed with aqueous citric acidsolution, saturated aqueous NaHCO₃ solution and brine, dried (Na₂SO₄)and concentrated. The crude material was crystallized in hexanes/EtOActo give the title compound as white solid. t_(R): 1.27 min (LC-MS 1);ESI-MS: 491.1 [M+H]⁺ (LC-MS 1).

Step F12-Bromo-5-[(4-chloro-2-methyl-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 with the product from step F2 as starting material; ESI-MS:512.1 [M+H]⁺ (LC-MS 1); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.28 (s, 1H),7.18 (d, 1H), 6.95-6.88 (m, 2H), 6.69 (s, 1H), 6.50 (s, 1H), 4.84-4.79(m, 1H), 2.33 (s, 3H), 2.03 (3H), 1.50 (bs, 3H), 1.29 (bs, 3H).

Step F22-Bromo-5-[(4-chloro-2-methyl-phenyl)-5-chloro-2-methyl-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate C) and 2-methyl-5-chloroaniline asstarting materials. t_(r): 1.46 min (LC-MS 1); ESI-MS: 540.2 [M+H]⁺(LC-MS 1); ¹H-NMR (DMSO-d₆, 400 MHz) δ □ ppm 7.36 (s, 1H), 7.23 (d, 1H),6.97 (dd, 2H), 6.73 (bs, 1H), 6.58 (d, 1H), 6.35 (s, 1H), 5.91 (d, 1H),5.02 (sep, 1H), 4.21 (q, 2H), 2.19 (s, 3H), 2.09 (s, 3H), 1.38 (d, 3H),1.31 (d, 3H), 1.22 (t, 3H).

Intermediate G2-Bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F using the product from step G1 as starting material.t_(R): 1.19 min (LC-MS 1); ESI-MS: 484.0 [M+H]⁺ (LC-MS 1).

Step G12-Bromo-5-[(3-chloro-2-fluoro-phenyl)-4-chloro-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 with the product from step G2 as starting material; ESI-MS:502.2 [M+H]⁺ (LC-MS 1); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.46 (d, 2H),7.29 (d, 2H), 6.99 (dd, 1H), 6.82 (d, 1H), 6.73-6.69 (m, 2H), 4.82 (sep,1H), 1.45 (d, 3H), 1.18 (d, 3H).

Step G22-Bromo-5-[(3-chloro-2-fluoro-phenyl)-4-chloro-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and 2-fluoro-3-chloro-aniline asstarting materials; ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.46 (d, 2H), 7.30(d, 2H), 6.98 (dd, 1H), 6.82 (d, 1H), 6.73-6.69 (m, 2H), 4.82 (sep (1H),4.26 (q, 2H), 1.45 (d, 3H), 1.24 (t, 3H), 1.17 (d, 3H).

Intermediate H4-[2-Bromo-5-(5-chloro-2-methyl-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate E using the product from step H1 as starting material.t_(R): 1.09 min (LC-MS 2); ESI-MS: 469.3 [M+H]⁺ (LC-MS 2).

Step H12-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 with the product from step H2 as starting material. t_(R):1.13 min (LC-MS 2); ESI-MS: 486.9 [M−H]⁺ (LC-MS 2).

Step H22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (step H3) and 5-chloro-2-methyl-aniline as startingmaterials. t_(R): 1.35 min (LC-MS 2); ESI-MS: 515.2 [M−H]⁺ (LC-MS 2);R_(f)=0.16 (hexane/EtOAc, 3:1).

Step H32-Bromo-5-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

LDA (2 M in THF, 53.6 mL, 107 mmol) was added slowly (over 30 min) to acold (−78° C.) solution of intermediate A (20 g, 77 mmol) in THF (400mL) (during the addition, the temperature raised to −70° C.). Themixture was stirred for 1 h at −78° C. A solution of 4-cyanobenzaldehyde(14 g, 107 mmol) in THF (100 mL) was added slowly. The reaction mixturewas stirred for 30 min at −78° C., allowed to warm to −20° C. over 1 h,quenched by addition of acetic acid (10 mL), diluted with EtOAc/water,and extracted with EtOAc. The organic extracts were washed with waterand brine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 1:1), followed bytrituration in EtOAc, to provide 20.1 g of the title compound. t_(R):0.99 min (LC-MS 2); ESI-MS: 392.2/394.1 [M+H]⁺ (LC-MS 2); R_(f)=0.29(hexane/EtOAc, 1:1).

Intermediate I2-Bromo-6-(4-chloro-2-methyl-phenyl)-5-(4-chloro-pyridinyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F with the product from step I1 as starting material.t_(R): 1.38 min (LC-MS 1); ESI-MS: 481.0 [M+H]⁺ (LC-MS 1); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.27 (d, 1H), 8.23 (s, 1H), 7.36 (s, 1H), 7.19(d, 1H), 7.12 (d, 1H), 6.87 (s, 1H), 6.75 (d, 1H), 4.49 (sep, 1H), 2.80(s, 3H); 1.36 (d, 3H), 0.69 (d, 3H).

Step I12-Bromo-5-[(4-chloro-2-methyl-phenyl)-(4-chloro-pyridin-2-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 using the product from step I2 as starting material. t_(R):1.24 min (LC-MS 1); ESI-MS: 499.2 [M+H]⁺ (LC-MS 1); ¹H-NMR (DMSO-d₆, 400MHz) δ ppm 7.91 (d, 1H), 7.57 (bs, 1H), 7.33 (s, 1H), 7.21 (d, 1H), 7.11(bs, 1H), 7.00 (d, 1H), 6.65 (s, 1H), 6.63 (d, 1H), 4.72 (sep, 1H), 2.16(s, 3H), 1.43 (d, 3H), 0.99 (d, 3H).

Step I22-Bromo-5-[(4-chloro-2-methyl-phenyl)-(4-chloro-pyridin-2-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate C) and 2-amino-4-chloro-pyridine asstarting materials. t_(R): 1.42 min (LC-MS 1); ESI-MS: 527.2 [M+H]⁺(LC-MS 1).

Intermediate J2-Bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F using the product from step J1 as starting material.t_(R): 0.97 min (LC-MS 2); ESI-MS: 497.1 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 7.88 (s, 2H), 7.46 (d, 2H), 7.24 (d, 2H), 6.43(s, 1H), 4.55 (sep, 1H), 3.45 (s, 3H), 1.42 (d, 3H), 0.68 (d, 3H).

Step J12-Bromo-5-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 using the product from step J2. t_(R): 0.94 min (LC-MS 2);ESI-MS: 515.1 [M+H]⁺ (LC-MS 2). ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.64 (s,1H), 7.46 (d, 2H), 7.35 (s, 1H), 7.33 (d, 2H), 6.47 (bs, 1H), 4.61 (sep,1H), 3.47 (s, 3H), 1.34 (d, 3H), 1.27 (d, 3H).

Step J22-Bromo-5-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and the product from step J3 asstarting materials. t_(R): 1.09 min (LC-MS 2); ESI-MS: 543.2 [M+H]⁺(LC-MS 2).

Step J3 5-Amino-3-chloro-1-methyl-1H-pyridin-2-one

A mixture of the compound prepared in step J4 (3.4 g, 18.1 mmol), ironpowder (3 g, 54.3 mmol), EtOH (68 mL) and an aqueous saturated NH₄Clsolution (17 mL) was stirred for 1 h at reflux. The reaction mixture wasallowed to cool to rt, filtered through a pad of celite andconcentrated. The residue was purified by flash chromatography(CH₂Cl₂/MeOH, 97:3) to provide 2.7 g of the title compound; ESI-MS: 159[M+H]⁺ (LC-MS 2); R_(f=0.06) (CH₂Cl₂/MeOH, 95:5). ¹H-NMR (DMSO-d₆, 400MHz) □δ ppm 7.36 (s, 1H), 6.88 (s, 1H), 4.42 (bs, 2H), 3.36 (s, 3H).

Step J4 3-Chloro-1-methyl-5-nitro-1H-pyridin-2-one

Methyl iodide (0.12 mL, 1.73 mmol) was added to a cold (0° C.) mixtureof 3-chloro-2-hydroxy-5-nitropyrindine (0.2 g, 1.15 mmol) and K₂CO₃(0.32 g, 2.23 mmol) in DMF (5 mL). The reaction mixture was allowed towarm to rt, stirred for 2 h, quenched by addition of water, andextracted with EtOAc. The organic phase was washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude material was purified byflash chromatography (hexane/EtOAc, 9:1) to afford 0.136 g of the titlecompound. t_(R): 0.64 min (LC-MS 2); ESI-MS: 189 [M+H]⁺ (LC-MS 2);R_(f)=0.50 (hexane/EtOAc, 1:1).

Intermediate K 5-N-Methyl-carboxamido-2-methoxy-phenyl boronic acid

5-Carboxy-2-methoxyphenyl boronic acid (200 mg, 1.0 mmol) was dissolvedin DMF (6 mL) and methylamine (2 M solution in THF, 2.0 mmol) was addedfollowed by HATU (430 mg, 1.1 mmol) and NMM (450 μL, 4.0 mmol). Thereaction mixture was allowed to stir at rt for 2 days and concentrated.The residue diluted in EtOAc and the organic phase washed with brine,dried and concentrated to give the crude product which wasrecrystallized in DCM to give the title compound as a white solid;ESI-MS: 210.1 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.23(bs, 1H), 8.00 (s, 1H), 7.84 (d, 1H), 6.99 (d, 1H), 3.81 (s, 3H), 2.73(s, 3H).

Intermediate L 5-N-(2-Hydroxyethyl)-carboxamido-2-methoxy-phenyl boronicacid

The title compound was prepared in analogy to the procedure describedfor Intermediate K using 5-carboxy-2-methoxyphenyl boronic acid andethanolamine; ESI-MS: 240.2 [M+H]⁺ LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δppm 8.60 (bs, 1H), 8.30 (s, 1H), 7.96 (d, 1H), 7.08 (d, 1H), 3.85 (s,3H), 3.55-3.48 (m, 2H), 3.35-3.30 (m, 2H).

Intermediate M 5-N,N-Dimethyl-carboxamido-2-methoxy-phenyl boronic acid

The title compound was prepared in analogy to the procedure describedfor intermediate K using 5-carboxy-2-methoxyphenyl boronic acid anddimethylamine (2M solution in THF); ESI-MS: 223.2 [M+H]⁺ (LC-MS 2);¹H-NMR (DMSO-d₆, 400 MHz) δ 7.83 (s, 1H), 7.58 (s, 1H), 7.46 (d, 1H),7.02 (d, 1H), 3.83 (s, 3H), 2.51 (s, 6H).

Intermediate N: 5-N-Isopropyl-carboxamido-2-methoxy-phenyl boronic acid

The title compound was prepared in analogy to the procedure describedfor intermediate K using 5-carboxy-2-methoxyphenyl boronic acid andisopropylamine; ESI-MS: 238.2 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400MHz) δ 8.08 (d, 1H), 8.03 (s, 1H), 7.90 (d, 1H), 7.00 (d, 1H), 4.21(sept, 1H), 3.84 (s, 3H), 1.15 (d, 6H).

Intermediate O 5-Morpholine-carbonyl-2-methoxy-phenyl boronic acid

The title compound was prepared in analogy to the procedure describedfor intermediate K using 5-carboxy-2-methoxyphenyl boronic acid andmorpholine; ESI-MS: 266.5 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ7.84 (s, 1H), 7.57 (d, 1H), 7.46 (d, 1H), 7.03 (d, 1H), 3.83 (s, 3H),3.62-3.60 (m, 4H), 3.49-3.42 (m, 4H).

Intermediate P 5-(3-Hydroxy-azetidine)-carbonyl-2-methoxy-phenyl boronicacid

The title compound was prepared in analogy to the procedure describedfor intermediate K using 5-carboxy-2-methoxyphenyl boronic acid and2-hydroxy-azetidine. t_(R): 0.45 min (LC-MS 2); ESI-MS: 254.4 [M+H]⁺(LC-MS 2).

Intermediate Q2-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F with the product from step Q1. t_(R): 1.21 min (LC-MS2); ESI-MS: 484.1 [M+H]⁺ (LC-MS 2).

Step Q12-Bromo-5-[(3-chloro-4-fluoro-phenyl)-4-chloro-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1. t_(R): 1.20 min (LC-MS 2); ESI-MS: 502.0 [M+H]⁺ (LC-MS 2);¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.46 (d, 2H), 7.32 (d, 2H), 7.09 (dd,1H), 6.89 (d, 1H), 6.71 (d, 1H), 4.57 (bs, 1H), 4.01 (sep, 1H), 1.36 (d,3H), 1.17 (d, 3H).

Step Q22-Bromo-5-[(3-chloro-4-fluoro-phenyl)-4-chloro-phenylamino]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and 3-chloro-4-fluoro-aniline asstarting materials. t_(R): 1.38 min (LC-MS 2); ESI-MS: 530.1 [M+H]⁺(LC-MS 2).

Intermediate R 4-(Hydroxymethyl)-2-methoxy-phenyl boronic acid

4-Carboxy-2-methoxyphenylboronic acid (500 mg, 2.5 mmol) was dissolvedin THF (25 mL) and cooled to 0° C. At this temperature LAH (2 M solutionin THF; 3.3 mL, 6.6 mmol) was added drop wise and the reaction mixtureallowed to stir for 1 h at 0° C. and then allowed to warm to rt andstirred for 16 h. The reaction mixture was recooled to 0° C. andquenched by addition of MeOH. Celite and Na₂SO₄ were added, stirred for15 min and then filtered. The filtrate was concentrated and the residuewas dried under high vacuum to give the title compound which was usedwithout further purification. t_(R): 0.46 min (LC-MS 2).

Intermediate S3-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2ylbenzonitrile

4-Bromo-3-methoxy-benzonitrile (300 mg, 1.4 mmol) was dissolved indioxane (2.5 mL) and the solution was flushed with argon.Bis-pinacolatodiboron (719 mg, 2.8 mmol), Pd(dppf)Cl₂ (58 mg, 0.07 mmol)and KOAc (417 mg, 4.2 mmol) were added and the reaction mixture washeated to 100° C. and stirred at this temperature for 19 h. It was thenallowed to cool to rt and diluted with EtOAc. The organic phase waswashed with brine, dried (Na₂SO₄) and concentrated. The residual crudeproduct was purified by flash chromatography (25 g silica gel cartridge,hexanes/EtOAc, 100:0→60:40) to give the title compound as a white solid;¹H-NMR (DMSO-d, 400 MHz) δ ppm 7.68 (d, 1H), 7.42 (s, 1H), 7.39 (d, 1H),3.82 (s, 3H), 1.32 (s, 12H).

Intermediate T4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine

A mixture of the compound prepared in step T1 (3 g, 15.9 mmol),bis(pinacolato)diboron (4.43 g, 17.5 mmol), PdCl₂(dppf)-CH₂Cl₂ complex(0.648 g, 0.794 mmol) and KOAc (4.67 g, 47.6 mmol) in DMSO (2 mL) washeated to 100° C. under argon and stirred for 2 h, allowed to cool tort, diluted with EtOAc/water, and extracted with EtOAc. The organiclayer was washed with water and brine, dried (Na₂SO₄), filtered, andconcentrated. The residue was boiled in Et₂O and filtered. The filtratewas concentrated, triturated in hexane, and filtered to afford 1.19 g ofthe title compound. For the corresponding boronic acid. t_(R): 0.36 min(LC-MS 2); ESI-MS: 155.1 [M+H]⁺ (LC-MS 2).

Step T1 5-Bromo-4-methoxy-pyrimidine

A mixture of the compound prepared in step T2 (3.13 g, 17.9 mmol) andPOCl₃ (16.7 mL, 179 mmol) was stirred for 1 h at 80° C. andconcentrated. The residue was dissolved in CH₂Cl₂ (30 mL) and cooled to5° C. MeOH (20 mL) was added. The mixture was stirred for 1 h at rt andconcentrated. The residue was triturated in CH₂Cl₂ to afford 3.2 g ofthe title compound; API-MS: 189.0 [M+H]⁺.

Step T2 5-Bromo-3H-pyrimidin-4-one

A mixture of 3H-pyrimidin-4-one (11 g, 114 mmol), bromine (6.5 mL, 126mmol), and KOAc (33.7 g, 343 mmol) in AcOH (100 mL) was stirred for 30min at rt. The resulting precipitate was collected by filtration toprovide 30 g of a white solid. This solid was dissolved in CH₂Cl₂/water,extracted with CH₂Cl₂/MeOH (9:1). The organic layer was dried (Na₂SO₄),filtered, and concentrated to afford 3.1 g of the title compound(compound was soluble in water and stayed in the aqueous layer despiterepeated extractions). t_(R): 0.35 min (LC-MS 2); ESI-MS: 175.0 [M+H]⁺(LC-MS 2).

Intermediate U4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine

A mixture of 5-bromo-4-methoxypyrimidin-2-amine (2.27 g, 11.1 mmol),bis(pinacolato)diboron (3.1 g, 12.2 mmol), PdCl₂(dppf)-CH₂Cl₂ complex(0.453 g, 0.555 mmol) and KOAc (3.27 g, 33.3 mmol) in dioxane (60 mL)was stirred at 115° C. for 20 h under argon, allowed to cool to rt,diluted with toluene (60 mL), sonicated, and filtered through a pad ofcelite. The filter cake was rinsed with hot toluene. The filtrate wasconcentrated to afford 3.9 g (30% purity) of the title compound whichwas used without purification. For the corresponding boronic acid.t_(R): 0.22 min (LC-MS 2); ESI-MS: 170.1 [M+H]⁺ (LC-MS 2).

Intermediate V4-Ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate T but using 2 equivalents of3-bromo-4-ethylbenzonitrile (Wagner, P. J.; Wang, L. Organic Letters,2006, 8, 645-647), and stirring the reaction mixture for 4 h at 100° C.The reaction mixture was quenched by addition of a saturated aqueoussolution of NaHCO₃, and filtered through a pad of celite. The filtratewas extracted with EtOAc. The organic layer was washed with a saturatedaqueous solution of NaHCO₃, dried (Na₂SO₄), filtered, and concentrated.The residue was purified by flash chromatography (hexane/EtOAc,1:0→92:8) to afford the title compound (75% purity). t_(R): 1.39 min(LC-MS 2); ESI-MS: 275.4 [M+18]⁺ (LC-MS 2).

Intermediate W[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-dimethyl-amine

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step W1, 0.1equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 10 h at 105° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated, and filtered. The filter cake wasrinsed with hot toluene. The filtrate was concentrated to afford thetitle compound (50% purity) which was used without purification. For thecorresponding boronic acid. t_(R): 0.40 min (LC-MS 2); ESI-MS: 198.1[M+H]⁺ (LC-MS 2).

Step W1 (5-Bromo-4-methoxy-pyrimidin-2-yl)-dimethyl-amine

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3 g, 13.4 mmol) anddimethylamine (2 M in THF, 33.6 mL, 67.1 mmol) in THF (20 mL) wasstirred for 18 h at rt and concentrated. The residue was purified byflash chromatography (hexane/EtOAc, 9:1) to afford 2.95 g of the titlecompound. t_(R): 1.04 min (LC-MS 2); ESI-MS: 232.0/234.0 [M+H]⁺ (LC-MS2); R_(f): 0.34 (hexane/EtOAc 9:1).

Intermediate X2-{[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amino}-ethanol

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step X1, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 8 h at 110° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated, and filtered. The filter cake wasrinsed with hot toluene. The filtrate was concentrated to give the titlecompound (50% purity) which was used without purification. For thecorresponding boronic acid. t_(R): 0.38 min (LC-MS 2); ESI-MS: 228.2[M+H]⁺ (LC-MS 2).

Step X1 2-[(5-Bromo-4-methoxy-pyrimidin-2-yl)-methyl-amino]-ethanol

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and2-(methylamino)ethanol (2.19 g, 29.1 mmol) in THF (40 mL) was stirredfor 18 h at rt and concentrated. The residue was purified by flashchromatography (hexane/EtOAc, 3:2) to afford 5.38 g of the titlecompound. t_(R): 0.84 min (LC-MS 2); ESI-MS: 262.1/264.1 [M+H]⁺ (LC-MS2); R_(f): 0.15 (hexane/EtOAc 3:2).

Intermediate Y2-[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamino]-ethanol

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step Y1, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 4 h at 110° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated, and filtered. The filter cake wasrinsed with hot toluene. The filtrate was concentrated to give the titlecompound (30% purity) which was used without purification. t_(R): 0.38min (LC-MS 2); API-MS: 296.1 [M+H]⁺ (LC-MS 2).

Step Y1 2-(5-Bromo-4-methoxy-pyrimidin-2-ylamino)-ethanol

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and2-amino ethanol (1.76 mL, 29.1 mmol) in THF (50 mL) was stirred for 18 hat rt. 2-Amino ethanol (2 mL) was added. The reaction mixture wasstirred for 18 h at rt and concentrated. The residue was purified byflash chromatography (hexane/EtOAc, 3:2) to afford 4.08 g of the titlecompound. t_(R): 0.70 min (LC-MS 2); ESI-MS: 248.2 [M+H]⁺ (LC-MS 2);R_(f): 0.06 (hexane/EtOAc 3:2).

Intermediate Z[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-methyl-amine

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step Z1, 0.1equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 16 h at 105° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated for 30 min, and filtered. The filtercake was rinsed with hot toluene. The filtrate was concentrated. Theresidue was diluted in hexane, sonicated for 30 min, filtered, andconcentrated to give the title compound (50% purity) which was usedwithout purification. For the corresponding boronic acid. t_(R): 0.35min (LC-MS 2); ESI-MS: 184.2 [M+H]⁺ (LC-MS 2).

Step Z1 (5-Bromo-4-methoxy-pyrimidin-2-yl)-methyl-amine

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3 g, 13.4 mmol) andmethylamine (2 M in THF, 50 mL, 100 mmol) in THF (20 mL) was stirred for40 h at rt and concentrated. The residue was purified by flashchromatography (hexane/EtOAc, 1:1) to afford 2.5 g of the titlecompound. t_(R): 0.81 min (LC-MS 2); ESI-MS: 218/220.1 [M+H]⁺ (LC-MS 2);R_(f): 0.39 (hexane/EtOAc 1:1).

Intermediate AA4-[2-Bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-isopropyl-6-oxo-5,6-dihydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

A mixture of the compound prepared in step AA1 (541 mg, 1.1 mmol), TBTU(482 mg, 1.5 mmol), DIEA (0.562 mL, 3.2 mmol) in DMF (6 mL) was stirredat 80° C. for 1 h. The reaction mixture was diluted in EtOAc/water,extracted twice with EtOAc and the combined organic extracts were washedwith water and brine, dried (Na₂SO₄) and concentrated. The residue waspurified by trituration in EtOAc to afford 385 mg of the title compound.t_(R): 0.83 min (LC-MS 2); ESI-MS: 486.1/488.2 [M+H]⁺ (LC-MS 2).

Step AA12-Bromo-5-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

A mixture of the compound prepared in step AA2 (675 mg, 1.27 mmol) andNaOH (2 M in water, 5 mL, 10 mmol) in THF (5 mL) and MeOH (5 mL) wasstirred for 30 min at rt. THF and MeOH were evaporated. The resultingmixture was diluted in EtOAc/water, and pH was adjusted to 5 withdiluted HCl. The aqueous layer was separated and extracted with EtOAc.The combined organic layers were dried (Na₂SO₄) and concentrated toprovide 545 mg of the title compound. t_(R): 0.81 min (LC-MS 2); ESI-MS:504.2/506.2 [M+H]⁺ (LC-MS 2).

Step AA22-Bromo-5-[(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

Ms₂O (1.05 g, 6.05 mmol) was added to a cold (5° C.) solution of thecompound prepared in step H3 (1.19 g, 3.02 mmol) and Et₃N (2.1 mL, 15.1mmol) in CH₂Cl₂ (25 mL) under argon. The mixture was stirred for 15 minat 5° C. The compound prepared in Step J3 (719 mg, 4.54 mmol) was added.The reaction mixture was allowed to warm to rt, stirred for 48 h,diluted with CH₂Cl₂/water and extracted with CH₂Cl₂. The organicextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash chromatography(CH₂Cl₂/EtOAc, 1:1), followed by trituration in Et₂O to provide 681 mgof the title compound. t_(R): 0.96 min (LC-MS 2); ESI-MS: 532.2/534.1[M+H]⁺ (LC-MS 2); R_(f): 0.14 (CH₂Cl₂/EtOAc 1:1).

Intermediate AB4-[2-Bromo-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-5,6-dihydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

A mixture of the compound prepared in step AB1 (2 g, 4.07 mmol), TBTU(1.83 g, 5.69 mmol), DIEA (2.1 mL, 12.2 mmol) in DMF (20 mL) was stirredat 80° C. for 10 h. The reaction mixture was diluted in EtOAc/water,extracted twice with EtOAc and the combined organic extracts were washedwith water and brine, dried (Na₂SO₄), filtered and concentrated. Thecrude was purified twice by flash chromatography (CH₂Cl₂/EtOAc85:15→30:70) to afford 350 mg of the title compound. t_(R): 1.07 min(LC-MS 2); ESI-MS: 473.2/475.2 [M+H]⁺ (LC-MS 2); R_(f)=0.23(CH₂Cl₂/EtOAc, 85:15).

Step AB12-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

A mixture of the compound prepared in step AB2 (4.92 g, 9.47 mmol) andNaOH (2 M in water, 30 mL, 60 mmol) in THF (30 mL) and MeOH (30 mL) wasstirred for 30 h at rt. THF and MeOH were evaporated. The resultingmixture was diluted in EtOAc/water, and pH was adjusted to 5 withdiluted HCl. The aqueous layer was separated and extracted with EtOAc.The combined organic layers were dried (Na₂SO₄), filtered andconcentrated. The residue was triturated in Et₂O to provide 4.02 g ofthe title compound. t_(R): 1.10 min (LC-MS 2); ESI-MS: 491.2/493.1[M+H]⁺ (LC-MS 2).

Step AB22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

Ms₂O (3.55 g, 20.4 mmol) was added to a cold (5° C.) solution of thecompound prepared in step H3 (4 g, 10.2 mmol) and Et₃N (7.1 mL, 51 mmol)in CH₂Cl₂ (80 mL) under argon. The mixture was stirred for 30 min at 5°C. 3-Chloro-2-fluoroaniline (2.23 g, 15.3 mmol) was added. The reactionmixture was allowed to warm to rt, stirred for 40 h, diluted withCH₂Cl₂/water and extracted with CH₂Cl₂. The organic extracts were washedwith brine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 7:3), followed bytrituration in Et₂O, to provide 4.93 g of the title compound. t_(R):1.28 min (LC-MS 2); ESI-MS: 519.2/521.0 [M+H]⁺ (LC-MS 2); R_(f): 0.20(hexane/EtOAc 7:3).

Intermediate AC4-[2-Bromo-5-(3-chloro-4-fluoro-phenyl)-3-isopropyl-6-oxo-5,6-dihydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

A mixture of the compound prepared in step AC1 (3.3 g, 6.71 mmol), TBTU(3.02 g, 9.40 mmol), DIEA (3.5 mL, 20.1 mmol) in DMF (33 mL) was stirredat 80° C. for 5 h. The reaction mixture was diluted in EtOAc/water,extracted twice with EtOAc and the combined organic extracts were washedwith water and brine, dried (Na₂SO₄), filtered, and concentrated. Thecrude was purified twice by flash chromatography (CH₂Cl₂/EtOAc 30:70),followed by trituration in EtOAc, to afford 1.46 g of the titlecompound. t_(R): 1.09 min (LC-MS 2); ESI-MS: 473.1/475.1 [M+H]⁺ (LC-MS2); R_(f)=0.22 (CH₂Cl₂/EtOAc 30:70).

Step AC12-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

A mixture of the compound prepared in step AC2 (4.54 g, 8.73 mmol) andNaOH (2 M in water, 30 mL, 60 mmol) in THF (30 mL) and MeOH (30 mL) wasstirred for 30 min at rt. THF and MeOH were evaporated. The resultingmixture was diluted in EtOAc/water, and pH was adjusted to 5 withdiluted HCl. The aqueous layer was separated and extracted with EtOAc.The combined organic layers were dried (Na₂SO₄), filtered, andconcentrated. The residue was triturated in Et₂O to provide 3.3 g of thetitle compound. t_(R): 1.11 min (LC-MS 2); ESI-MS: 491.2/493.2 [M+H]⁺(LC-MS 2).

Step AC22-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

Ms₂O (3.55 g, 20.4 mmol) was added to a solution of the compoundprepared in step H3 (4 g, 10.2 mmol) and Et₃N (7.1 mL, 51 mmol) inCH₂Cl₂ (80 mL) at rt, under argon. The mixture was stirred for min atrt. 3-Chloro-4-fluoroaniline (2.23 g, 15.3 mmol) was added. The reactionmixture was stirred for 40 h at rt, diluted with CH₂Cl₂/water, andextracted with CH₂Cl₂. The organic extracts were washed with brine,dried (Na₂SO₄), filtered, and concentrated. The residue was purified byflash chromatography (hexane/EtOAc 7:3) to provide 4.60 g of the titlecompound. t_(R): 1.25 min (LC-MS 2); ESI-MS: 519.2/521.2 [M+H]⁺ (LC-MS2); R_(f): 0.16 (hexane/EtOAc, 7:3).

Intermediate AD1-[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2-]dioxaborolan-2-yl)-pyrimidin-2-yl]-3-methyl-azetidin-3-ol

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step AD1, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 4 h at 110° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated, and filtered. The filter cake wasrinsed with hot toluene. The filtrate was concentrated to give the titlecompound (30% purity) which was used without purification. For theboronic acid. t_(R): 0.40 min (LC-MS 2); ESI-MS: 240.2 [M+H]⁺ (LC-MS 2).

Step AD1 1-(5-Bromo-4-methoxy-pyrimidin-2-yl)-3-methyl-azetidin-3-ol

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.5 g, 15.7 mmol),3-methylazetidin-3-ol hydrochloride (2.90 g, 23.5 mmol), and Et₃N (4.4mL, 31.3 mmol) in THF (50 mL) was stirred for 18 h at rt.3-Methylazetidin-3-ol hydrochloride (1 g) was added. The reactionmixture was stirred for 72 h at rt and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc 1:1) to afford 2.5 g ofthe title compound. t_(R): 0.81 min (LC-MS 2); ESI-MS: 274.2 [M+H]⁺(LC-MS 2); R_(f): 0.25 (hexane/EtOAc 1:1).

Intermediate AE1-[4-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-azetidin-3-ol

The title compound was prepared in analogy to the procedure describedfor intermediate U but using the compound prepared in step AE1, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 4 h at 110° C. The reaction mixture was allowed to cool tort, diluted with toluene, sonicated, and filtered. The filter cake wasrinsed with hot toluene. The filtrate was concentrated to give the titlecompound (30% purity) which was used without purification. For theboronic acid. t_(R): 0.36 min (LC-MS 2); ESI-MS: 226.2 [M+H]⁺ (LC-MS 2).

Step AE1 1-(5-Bromo-4-methoxy-pyrimidin-2-yl)-azetidin-3-ol

A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (3.3 g, 14.8 mmol),3-hydroxyazetidine hydrochloride (3.2 g, 29.5 mmol), and Et₃N (4.3 mL,31.0 mmol) in THF (50 mL) was stirred for 18 h at rt. 3-Hydroxyazetidinehydrochloride (1 g) was added. The reaction mixture was stirred for 24 hat rt and concentrated. The residue was diluted in CH₂Cl₂/water andextracted with CH₂Cl₂. The combined organic extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated. The crude materialwas purified by flash chromatography (hexane/EtOAc, 1:1) to afford 3 gof the title compound. t_(R): 0.73 min (LC-MS 2); ESI-MS: 260.1/262.1[M+H]⁺ (LC-MS 2); R_(f=0.18) (hexane/EtOAc 1:1).

Intermediate AF2-Bromo-6-(4-chloro-phenyl)-5-(5-chloro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F with the product from step AF1 as starting material.t_(R): 1.14 min (LC-MS2); ESI-MS: 465.1/467.1 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₅, 400 MHz) δ ppm 8.76 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H),7.49-7.44 (m, 4H), 6.87 (s, 1H), 4.56 (sep, 1H), 1.47 (d, 3H), 0.66 (d,3H).

Step AF12-Bromo-5-[(4-chloro-2-methyl-phenyl)-(5-chloro-pyridin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step AA1 using the product from step AF2 as starting material.t_(R): 1.03 min (LC-MS 2); ESI-MS: 483.0/485.0 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.19 (s, 1H), 7.89 (s, 1H), 7.59 (bs, 1H), 7.48(d, 2H), 7.26 (d, 2H), 7.23 (s, 2H), 6.95 (bs, 1H), 4.47 (sep, 1H), 1.37(d, 3H), 1.17 (d, 3H).

Step AF22-Bromo-5-[(4-chloro-phenyl)-(5-chloro-pyridin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and 3-amino-5-chloro-pyridine asstarting materials. t_(R): 1.31 min (LC-MS 2); ESI-MS: 511.1/513.1[M+H]⁺ (LC-MS 2).

Intermediate AG2-Bromo-5-(3-chloro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F with the product from step AG1 as starting material.t_(R): 1.27 min (LC-MS2); ESI-MS: 464.0/466.1 [M+H]⁺ (LC-MS 2).

Step AG12-Bromo-5-[(4-chloro-phenyl)-(3-chloro-2-phenylamino)-methyl-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step AA1 using the product from step AG2 as starting material.t_(R): 1.19 min (LC-MS 2); ESI-MS: 481.8/484.0 [M+H]⁺ (LC-MS 2).

Step AG22-Bromo-5-[(4-chloro-phenyl)-(3-chloro-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and 3-chloro-aniline as startingmaterials. t_(R): 1.45 min (LC-MS 2); ESI-MS: 510.1/512.1 [M+H]⁺ (LC-MS2).

Intermediate AH 4-N,N-Dimethyl-carboxamido-2-methoxy-phenyl boronic acid

The title compound was prepared in analogy to the procedure describedfor intermediate K using 4-carboxy-2-methoxyphenyl boronic acid anddimethylamine (2M solution in THF). t_(R): 0.53 min (LC-MS 2); ESI-MS:223.2 [M+H]⁺ (LC-MS 2).

Intermediate AI2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E using the product from step AI1 as starting material.t_(r): 0.88 min (LC-MS 2); ESI-MS: 467.0 [M+H]⁺ (LC-MS 2).

Step AI12-Bromo-5-[(4-chloro-phenyl)-(1-methyl-6-oxo-piperidin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 with the product from step AI2 as starting material. t_(r):0.73 min (LC-MS 2); ESI-MS: 483.1 [M−H]⁺ (LC-MS 2).

Step AI22-Bromo-5-[(4-chloro-phenyl)-(1-methyl-6-oxo-piperidin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester (intermediate B) and 5-amino-1-methylpiperidin-2-one(ChemBridge, free base was made from the purchased HCl salt) as startingmaterials. The crude reaction mixture was diluted with EtOAc and washedwith aqueous NaHCO₃ solution and brine. t_(r): 1.07 min (LC-MS 2);ESI-MS: 511.1 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.42 (m,2H), 7.30 (m, 2H), 6.28 (NH, br, 1H), 4.85-5.00 (m, 1H), 4.25 (quin,2H), 3.15-3.05 (m, 2H), 2.84-2.75 (m, 1H), 2.72 (d, 3H), 2.38-1.85 (m,4H), 1.75-1.58 (m, 1), 1.45 (d, 3H), 1.24 (t, 3H), 0.83 (t, 3H).

Intermediate AK2-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a stirred solution of2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid (3-chloro-4-fluoro-phenyl)-amide (step AK1; 0.470 g, 0.907 mmol)and AcOH (4.53 ml) was added H₂SO₄ 98% (0.592 ml, 10.88 mmol). Thesolution was stirred for 7 h at 110° C. The reaction mixture wasconcentrated in vacuo. The residue was neutralized with 1M NaHCO₃ andextracted with EtOAc (2×). The organic phases were washed with brine anddried (Na₂SO₄), filtered and concentrated. The residue was purified byflash chromatography (hexane/EtOAc, 1:1), then triturated in diisopropylether/hexane to afford the title compound. t_(R): 1.29 min (LC-MS 2);ESI-MS: 496.0 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 7.79 (m,1H), 7.49 (m, 1H), 7.38 (s, 4H), 7.35 (m, 1H), 6.89 (s, 1H), 4.73 (m,1H), 2.45 (m, 2H), 1.86 (m, 1H), 1.63 (m, 1H), 1.42 (m, 2H).

Step AK12-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid (3-chloro-4-fluoro-phenyl)-amide

To the stirred solution of trimethylaluminium (2M in toluene) (0.87 ml,1.74 mmol) was added drop wise the solution of 3-chloro-4-fluoroaniline(0.267 g, 1.80 mmol) and toluene (2.0 ml) at 0° C. and then thetemperature was raised to rt. The mixture was concentrated.2-bromo-5-[(4-chloro-phenyl)-hydroxyl-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (step AK2; 0.502 g, 1.20 mol) in toluene (6.0 ml) wasadded and the mixture was stirred for 3 h at 80° C., then cooled to rt.The reaction mixture was taken up in Teac (40 ml), poured onto “RochelleSalt-Solution” (1M in water) and stirred for 15 min at rt. The organicphase was washed with brine and dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(EtOAc/hexane, 1:4), then triturated in hexane to afford the titlecompound. t_(R): 1.46 min (LC-MS 2); ESI-MS: 514.1 [M+H]⁺ (LC-MS 2).

Step AK22-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate B using 2-bromo-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (step AK3) and 4-chlorobenzaldehyde. t_(R): 1.21 min(LC-MS 2); ESI-MS: 415.1 [M+H]⁺ (LC-MS 2).

Step AK3 2-Bromo-1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate A using 1-cyclobutyl-1H-imidazole-4-carboxylic acidethyl ester (step AK4). t_(R): 0.89 min (LC-MS 2); ESI-MS: 273.1/275.2[M+H]⁺ (LC-MS 2); TLC (EtOAc/n-heptane 1:5) R_(f)=0.49; ¹H-NMR (DMSO-d₆,400 MHz) δ ppm 8.25 (s, 1H), 4.68 (m, 1H), 4.20 (q, 2H), 2.40 (m, 4H),1.77 (m, 2H), 1.25 (t, 3H).

Step AK4 1-Cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester

The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethylester (17.0 g, 100 mmol) and cyclobutaneamine (21.79 g, 300 mmol) washeated for 2.5 h at 70° C. The reaction mixture was cooled to rt andconcentrated. The residue was purified by flash chromatography(EtOAc/hexane, 5:1) to afford the title compound as an orange oil.t_(R): 0.70 min (LC-MS 2); ESI-MS: 195.2 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.03 (s, 1H), 7.83 (s, 1H), 4.73 (m, 1H), 4.18(q, 2H), 2.36 (m, 4H), 1.74 (m, 2H), 1.24 (t, 3H).

Intermediate AL2-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained in analogy to the procedure describedfor intermediate AK and step AK1 using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (step AK2) and 3-chloro-4-fluoroaniline. t_(R): 1.28min (LC-MS 2); ESI-MS: 492.0 [M+H]⁺ (LC-MS 2).

Intermediate AM4-[2-Bromo-5-(3-chloro-4-fluoro-phenyl)-3-cyclobutyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained in analogy to the procedure describedfor intermediate F using2-bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid (step AM1). t_(R): 1.12 min (LC-MS 2); ESI-MS: 487.0 [M+H]⁻ (LC-MS2).

Step AM12-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid

The title compound was obtained in analogy to the procedure describedfor step AB1 using2-bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (step AM2). t_(R): 1.15 min (LC-MS 2); ESI-MS: 503.1[M+H]⁺ (LC-MS 2).

Step AM22-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor step AB2 using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (step AK2). t_(R): 1.33 min (LC-MS 2); ESI-MS: 533.1[M+H]⁺ (LC-MS 2).

Intermediate AN2-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained in analogy to the procedure describedfor intermediate AK using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid (3-chloro-4-fluoro-phenyl)-amide (step AN1). t_(R): 1.24 min (LC-MS2); ESI-MS: 482.0 [M+H]⁺ (LC-MS 2).

Step AN12-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid (3-chloro-4-fluoro-phenyl)-amide

The title compound was obtained in analogy to the procedure describedfor step AK1 using2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid ethyl ester (step AN2) and 3-chloro-4-fluoro-phenylamine. t_(R):1.40 min (LC-MS 2); ESI-MS: 500.0 [M+H]⁺ (LC-MS 2).

Step AN22-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid (3-chloro-4-fluoro-phenyl)-amide

The title compound was obtained in analogy to the procedure describedfor intermediate B using 2-bromo-1-cyclopropyl-1H-imidazole-4-carboxylicacid ethyl ester (step AN3) and 4-chlorobenzaldehyde. t_(R): 1.09 min(LC-MS 2); ESI-MS: 401.1 [M+H]⁺ (LC-MS 2).

Step AN3 2-Bromo-1-cyclopropyl-1H-imidazole-4-carboxylic acid ethylester

The title compound was obtained in analogy to the procedure describedfor intermediate A using 1-cyclopropyl-1H-imidazole-4-carboxylic acidethyl ester (step AN4). t_(R): 0.79 min (LC-MS 2); ESI-MS: 259.1/261.2[M+H]⁺ (LC-MS 2); TLC (EtOAc/n-heptane 1:5) R_(f)=0.49; ¹H-NMR (DMSO-de,400 MHz) δ ppm 7.95 (s, 1H), 4.19 (q, 2H), 3.37 (m, 1H), 1.23 (t, 3H),1.03 (d, 4H).

Step AN4 1-Cyclopropyl-1H-imidazole-4-carboxylic acid ethyl ester

The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethylester (17.0 g, 100 mmol) and cyclopropylamine (17.21 g, 300 mmol) washeated for 5 h at 75° C. The reaction mixture was cooled to rt andconcentrated. Purification of the residue by flash chromatography(EtOAc/hexane, 5:1) gave the title compound as an orange oil. t_(R):0.61 min (LC-MS 2); ESI-MS: 181.2 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400MHz) δ ppm 7.85 (s, 1H), 7.79 (s, 1H), 4.18 (q, 2H), 3.55 (m, 1H), 1.23(t, 3H), 0.91-1.02 (m, 4H).

Another embodiment of the invention provides a novel intermediatecompound as named, or described by structure, herein. Such compounds aredisclosed as “intermediate” or “step” compounds.

Example 15-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-fluoro-2-methoxy-phenyl)-1-isopropyl-4-oxo-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of intermediate F (60 mg, 0.12 mmol) in dioxane (2 ml)/H₂O(1 ml) were added 5-fluoro-2-methoxyphenylboronic acid (41 mg, 0.24mmol) and K₃PO₄ (103 mg, 0.48 mmol). The mixture was degassed for 5 minand then Pd(PPh₃)₄ (28 mg, 0.02 mmol) was added. The mixture was stirredat 100° C. for 1.5 h until complete conversion. Dioxane was removedunder reduced pressure. The residual suspension was diluted with EtOAcand extracted with brine. The aqueous layer was repeatedlyback-extracted with EtOAc. The combined organic extracts were dried(Na₂SO₄), filtered and concentrated. The remaining crude material waspurified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) to givethe title compound as a foam. t_(R): 1.33 min (LC-MS 2); ESI-MS:538.2/540.3 [M+H]⁺ (LC-MS 2).

Example 25-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(6-fluoro-2-methoxy-phenyl)-1-isopropyl-4-oxo-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 6-fluoro-2-methoxy-phenylboronicacid. t_(R): 1.32 min (LC-MS 2); ESI-MS: 538.3/540.2 [M+H]⁺ (LC-MS 2).

Example 35-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-trifluoromethoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2-trifluoro-methoxy-phenylboronicacid. t_(R): 1.38 min (LC-MS 2); ESI-MS: 574.3/576.3 [M+H]⁺ (LC-MS 2).

Example 43-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2-methoxy-5-cyano-phenylboronicacid. t_(R): 1.27 min (LC-MS 2); ESI-MS: 545.3/547.3 [M+H]⁺ (LC-MS 2).

Example 55-(5-Chloro-2-methyl-phenyl)-6-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2-methoxy-phenylboronic acid.t_(R): 1.29/1.32 min (LC-MS 2); ESI-MS: 520.2/522.3 [M+H]⁺ (LC-MS 2).

Example 65-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(4-methoxy-pyridin-3-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2-methoxy-pyridin-4-yl boronicacid. t_(R): 1.25/1.28 min (LC-MS2); ESI-MS: 521.2/523.2 [M+H]⁺ (LC-MS2).

Example 75-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.23/1.26 min (LC-MS 2); ESI-MS: 552.3/554.3 [M+H]⁺(LC-MS 2).

Example 85-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-methoxy-pyridin-3-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor Example 1 using intermediate F and 2-methoxy-pyridin-3-yl boronicacid. t_(R): 1.28 min (LC-MS 2); ESI-MS: 521.4/523.1 [M+H]⁺ (LC-MS 2).

Example 93-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate M. t_(R): 1.20 min(LC-MS 2); ESI-MS: 591.3/593.3 [M+H]⁺ (LC-MS 2).

Example 105-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N-methylbenzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate K. t_(R): 1.18 min(LC-MS 2); ESI-MS: 577.3/579.3 [M+H]⁺ (LC-MS 2).

Example 113-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxyethyl)-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate L. t_(R): 1.10/1.13min (LC-MS 2); ESI-MS: 607.3/609.3 [M+H]⁺ (LC-MS 2).

Example 123-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate N. t_(R): 1.23/1.26min (LC-MS); (LC-MS 2); ESI-MS: 605.3/607.3 [M+H]⁺ (LC-MS 2).

Example 135-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate O. t_(R): 1.16/1.19min (LC-MS 2); ESI-MS: 633.3/635.3 [M+H]⁺ (LC-MS 2).

Example 145-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[5-(3-hydroxy-azetidine-1-carbonyl)-2-methoxy-phenyl]1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate P. t_(R): 1.09/1.11min (LC-MS 2); ESI-MS: 619.3/621.2 [M+H]⁺ (LC-MS 2).

Example 155-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(3-methoxy-pyridin-4-yl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 2-methoxy-pyridin-4-yl boronicacid. t_(R): 1.16/1.19 min (LC-MS); ESI-MS: 521.3/523.3 [M+H]⁺ (LC-MS2).

Example 16 2-(5-Aminomethyl-2-methoxy-phenyl-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The product from example 4 (135 mg, 0.25 mmol) was dissolved in THF (3.5mL) and Raney Nickel (27 mg, 0.31 mmol) and aqueous NH₄OH solution (30%wt; 0.81 mL) were added. The reaction mixture was allowed to stir underan atmosphere of hydrogen at rt for 20 h. It was then filtered over apad of celite and concentrated under reduced pressure. The remainingcrude product was purified by preparative HPLC (Waters SunFire C18,30×100 mm; 0.1% TFA/acetonitrile, gradient acetonitrile 40-60%). t_(R):1.00/1.02 min (LC-MS 2); ESI-MS: 549.3/551.3 [M+H]⁺ (LC-MS 2).

Example 17N-{3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzyl}-acetamide

The product from example 16 (30 mg, 0.05 mmol) was dissolved in THF (0.7mL) and TEA (10 mL, 0.07 mmol) was added. The reaction was cooled in anice bath and acetyl chloride (5 mL, 0.06 mmol) was added. The coolingbath was removed and the reaction mixture allowed to stir at rt for 0.5h. It was then diluted with EtOAc and brine and the aqueous phaseextracted with EtOAc. The combined extracts were dried (Na₂SO₄) andconcentrated. The remaining crude product was triturated withacetonitrile to give the title compound as a white solid, which wasisolated by filtration and dried under reduced pressure. t_(R):1.18/1.21 min (LC-MS 2); ESI-MS: 591.2/593.2 [M+H]⁺ (LC-MS 2).

Example 185-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The product from step 18.1 (100 mg, 0.18 mmol) was dissolved in MeOH (3mL) at rt and NaBH₄ (11 mg, 0.27 mmol) was added. The reaction mixturewas allowed to stir at rt for 0.5 h and then diluted with EtOAc andwashed with brine. The aqueous layer was extracted with EtOAc, combinedorganic layers dried over Na₂SO₄ and concentrated. The residual crudematerial was purified by preparative HPLC (Waters SunFire C18, 30×100mm, 5 μm; 0.1% TFA-water/acetonitrile, gradient acetonitrile 50-70%, 16min). t_(R): 1.18/1.20 min (LC-MS2); ESI-MS: 550.3/552.3 [M+H]⁺ (LC-MS2).

Step 18.13-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxybenzaldehyde

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and 5-formyl-2-methoxy-phenylboronicacid. t_(R): 1.22/1.25 min (LC-MS2); ESI-MS: 548.3/550.3 [M+H]⁺ (LC-MS2).

Example 195-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in 2 steps in analogy to the proceduredescribed for example 18 using intermediate E and5-formyl-2-methoxy-phenylboronic acid. t_(R): 1.15 min (LC-MS2); ESI-MS:536.2/538.2 [M+H]⁺ (LC-MS 2).

Example 205-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the 2 steps proceduredescribed for example 18 using intermediate G and5-formyl-2-methoxy-phenylboronic acid. t_(R): 1.12 min (LC-MS2); ESI-MS:540.3/542.3 [M+H]⁺ (LC-MS 2).

Example 215-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(4-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate E and intermediate R. t_(R): 1.14 min(LC-MS2); ESI-MS: 536.2/538.2 [M+H]⁺ (LC-MS 2).

Example 225-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(4-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the 2 steps proceduredescribed for example 18 using intermediate F and intermediate R. t_(R):1.17/1.20 min (LC-MS); ESI-MS: 550.2/552.2 [M+H]⁺ (LC-MS 2).

Example 233-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide

The title compound was prepared in analogy to the procedure describedfor example 1 starting using intermediate E and intermediate M. t_(R):1.14 min (LC-MS); ESI-MS: 577.2/579.2 [M+H]⁺ (LC-MS 2). ¹H-NMR (DMSO-d₆,400 MHz) δ 7.79 (s, 1H), 7.63 (d, 1H), 7.48 (s, 1H), 7.39 (d, 2H), 7.31(d, 2H), 7.25 (d, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 6.62 (s, 1H), 4.04(sep, 1H), 3.83 (s, 3H), 2.97 (s, 6H), 1.94 (s, 3H), 1.31 (d, 3H), 0.52(bs, 3H).

Example 243-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 starting using intermediate E and5-cyano-2-methoxy-phenyl-boronic acid. t_(R): 1.22 min (LC-MS2); ESI-MS:531.2/533.2 [M+H]⁺ (LC-MS 2). ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.06 (d, 1H),7.94 (s, 1H), 7.79 (s, 1H), 7.42-7.38 (m, 3H), 7.32-7.28 (m, 2H), 7.19(d, 1H), 7.14 (d, 1H), 6.64 (s, 1H), 4.01 (sep, 1H), 3.88 (s, 3H), 1.95(s, 3H), 1.31 (d, 3H), 0.53 (bs, 3H).

Example 255-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 starting using intermediate E and intermediate O. t_(R):1.13 min (LC-MS 2); ESI-MS: 619.2/621.2 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ 8.06 (d, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.42-7.38(m, 3H), 7.32-7.28 (m, 2H), 7.19 (d, 1H), 7.14 (d, 1H), 6.64 (s, 1H),4.01 (sep, 1H), 3.88 (s, 3H), 1.95 (s, 3H), 1.31 (d, 3H), 0.53 (bs, 3H).

Example 264-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 starting using intermediate E and intermediate S. t_(R):1.23 min (LC-MS 2); ESI-MS: 531.1/533.2 [M+H]⁺ (LC-MS 2).

Example 275-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 starting using intermediate E and2,4-dimethoxy-pyrimidin-5-yl boronic acid. t_(R): 1.20 min (LC-MS 2);ESI-MS: 538.2/540.2 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ 8.51(s, 1H), 7.79 (s, 1H), 7.41-7.29 (m, 4H), 7.19-7.09 (m, 2H), 6.62 (s,1H), 4.15 (sep, 1H), 3.99 (s, 3H), 3.90 (s, 3H), 1.92 (s, 3H), 1.42 (d,3H), 0.49 (d, 3H).

Example 285-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(3,6-pyridazin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate E and 3,6-dimethoxy-pyridazin-4-ylboronic acid. t_(R): 1.20 min (LC-MS 2); ESI-MS: 538.2/540.2 [M+H]⁺(LC-MS 2).

Example 295-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

PdCl₂(dppf)-CH₂Cl₂ complex (33.1 mg, 0.041 mmol) was added to a heated(80° C.) mixture of intermediate F (200 mg, 0.405 mmol) and K₃PO₄ (344mg, 1.62 mmol) in dioxane (3 mL) and water (1 mL), under argon. Thetemperature was increased to 100° C. and 2,6-dimethoxypyridin-3-ylboronic acid (89 mg, 0.487 mmol) was added. The reaction mixture wasstirred for 15 min at 100° C., allowed to cool to rt, diluted withEtOAc/water, and extracted with EtOAc. The organic layer was washed withwater and brine, dried (Na₂SO₄), filtered, and concentrated. The residuewas purified by flash chromatography (hexane/EtOAc, 3:1), followed bytrituration in Et₂O/hexane (4:1), to afford 85 mg of the title compound.t_(R): 1.40 min (LC-MS 2); ESI-MS: 551.3/553.3 [M+H]⁺ (LC-MS 2); R_(f):0.31 (hexane/EtOAc, 3:1).

Example 305-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(4-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate T (2.3 equiv) and stirring thereaction mixture for 7 h at 100° C. After flash chromatography(CH₂Cl₂/MeOH, 95:5) of the crude product and subsequent trituration inEt₂O, the resulting material was further purified by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-70%B in 30 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.20 min (LC-MS 2);ESI-MS: 522.2/524.3 [M+H]⁺ (LC-MS 2); R_(f): 0.12 (CH₂Cl₂/MeOH, 95:5).

Example 315-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, intermediate Z (2 equiv), 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 30 min at 100° C. After flash chromatography (CH₂Cl₂/MeOH,95:5) of the crude product and subsequent trituration in Et₂O, theresulting material was further purified by preparative HPLC (Column:Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60% B in 30min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.22 min (LC-MS 2); ESI-MS:537.2/539.2 [M+H]⁺ (LC-MS 2); R_(f): 0.24 (CH₂Cl₂/MeOH, 95:5).

Example 325-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of2,6-dimethoxypyridin-3-yl boronic acid, 0.15 equivalents ofPdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reaction mixture for 30 minat 100° C. The crude product was purified by flash chromatography(hexane/EtOAc, 1:3) and subsequent trituration in Et₂O. t_(R): 1.35 min(LC-MS 2); ESI-MS: 537.2/539.2 [M+H]⁺ (LC-MS 2); R_(f): 0.32(hexane/EtOAc, 1:3).

Example 335-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,6-dimethoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of2-ethyl-6-methoxypyridin-3-ylboronic acid, 0.15 equivalents ofPdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reaction mixture for 30 minat 100° C. The crude product was purified by flash chromatography(hexane/EtOAc, 1:3) and subsequent trituration in Et₂O/hexane (1:4).t_(R): 1.38 min (LC-MS 2); ESI-MS: 535.3/537.2 [M+H]⁺ (LC-MS 2); R_(f):0.44 (hexane/EtOAc, 1:3).

Example 343-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-ethyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.8 equivalents of intermediateV, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 100° C. The crude product was purified byflash chromatography (hexane/EtOAc, 1:1) and subsequent trituration inEt₂O. t_(R): 1.34 min (LC-MS 2); ESI-MS: 529.2/531.2 [M+H]⁺ (LC-MS 2);R_(f): 0.14 (hexane/EtOAc, 1:1).

Example 355-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 2 equivalents of intermediate W, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 1 h at 100° C. After flash chromatography (CH₂Cl₂/MeOH,95:5) of the crude product and subsequent trituration in Et₂O, theresulting material was further purified by preparative HPLC (Column:Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60% B in 30min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.35/1.38 min (LC-MS 2);ESI-MS: 565.2/567.1 [M+H](LC-MS 2); R_(f): 0.25 (CH₂Cl₂/MeOH, 95:5).

Example 365-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 2 equivalents of intermediateW, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 1 h at 100° C. After flash chromatography(CH₂Cl₂/MeOH, 95:5) and subsequent trituration in Et₂O, the resultingmaterial was further purified by preparative HPLC (Column: Sunfire C18,30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60% B in 30 min; A=0.1%TFA in water, B=CH₃CN). t_(R): 1.33 min (LC-MS 2); ESI-MS: 551.2/553.2[M+H]⁺ (LC-MS 2); R_(f): 0.28 (CH₂Cl₂/MeOH, 95:5); ¹H NMR (DMSO-d, 400MHz) δ ppm 0.54 (d, J=6.3 Hz, 3H), 1.30 (d, J=7.0 Hz, 3H), [1.94 (br. s)and 2.24 (br. s), 3H, rotamers], 3.17 (s, 6H), 3.88 (s, 3H), 4.00-4.18(m, 1H), [6.11 (br. s) and 6.58 (br. s), 1H, rotamers], 7.10-7.40 (m,6H), 7.75 (br. s, 1H), 8.21 (s, 1H).

Example 372-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 2 equivalents of intermediateU, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 1 h at 100° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5) and subsequent trituration inEt₂O. t_(R): 1.13 min (LC-MS 2); ESI-MS: 523.2/525.2 [M+H]⁺ (LC-MS 2);R_(f): 0.13 (CH₂Cl₂/MeOH, 95:5); ¹H NMR (DMSO-d. 400 MHz) δ ppm 0.55 (d,J=6.26 Hz, 3H), 1.30 (d, J=6.65 Hz, 3H), [1.94 (br. s) and 2.24 (br. s),3H, rotamers], 3.83 (s, 3H), 4.10 (qd, J=6.71, 6.5 Hz, 1H), [6.10 (br.s) and 6.58 (br. s), 1H, rotamers], 7.00-7.45 (m, 8H), 7.76 (br. s, 1H),8.10 (s, 1H).

Example 385-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-4-methoxy-pyrimidin-5-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of intermediateX, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 2 h at 110° C. The crude product was loaded onto aVARIAN column PL-Thiol MP-Resin (to remove metal traces) and eluted withMeOH. The filtrate was concentrated and purified twice by flashchromatography (CH₂Cl₂/MeOH, 95:5). Trituration of the resultingmaterial in Et₂O/hexane (1:1) provided the title compound. t_(R): 1.19min (LC-MS 2); ESI-MS: 581.3/583.3 [M+H]⁺ (LC-MS 2); R_(f): 0.12(CH₂Cl₂/MeOH, 95:5).

Example 395-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(2-hydroxy-ethylamino)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of intermediateY, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 1.5 h at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 30 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.12 min(LC-MS 2); ESI-MS: 567.2/569.2 [M+H]⁺ (LC-MS 2); R_(f): 0.14(CH₂Cl₂/MeOH, 92.5:7.5).

Example 404-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H, 2 equivalents of intermediateU, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 2 h at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 0.98 min (LC-MS 2); ESI-MS: 514.3/516.2 [M+H]⁺ (LC-MS 2);R_(f): 0.29 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 414-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H, 2 equivalents of intermediateZ, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 1.06 min (LC-MS 2); ESI-MS: 528.3/530.3 [M+H]⁺ (LC-MS 2);R_(f): 0.33 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 424-[5-(5-Chloro-2-methyl-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H, 2 equivalents of intermediateW, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O/hexane (1:1). t_(R): 1.16 min (LC-MS 2); ESI-MS: 542.3/544.3 [M+H]⁺(LC-MS 2); R_(f): 0.25 (CH₂Cl₂/MeOH, 95:5).

Example 434-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AA, 2 equivalents of intermediateW, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 0.94 min(LC-MS 2); ESI-MS: 559.3/561.3 [M+H]⁺ (LC-MS 2); R_(f): 0.24(CH₂Cl₂/MeOH, 92.5:7.5).

Example 444-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AA, 2 equivalents of intermediateZ, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 15 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient5-50% B in 18 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 0.82 min (LC-MS 2); ESI-MS: 545.3/547.3 [M+H]⁺ (LC-MS 2);R_(f): 0.13 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 454-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AA, 2 equivalents of intermediateU, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 15 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient5-50% B in 18 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 0.73 min (LC-MS 2); ESI-MS: 531.3/533.3 [M+H]⁺ (LC-MS 2);R_(f): 0.09 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 465-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 2 equivalents of intermediate U, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 30 min at 100° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 30 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.25/1.27 min (LC-MS 2); ESI-MS: 551.2/553.2 [M+H]⁺ (LC-MS 2);R_(f): 0.24 (CH₂Cl₂/MeOH, 95:5).

Example 475-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-ethyl-6-methoxy-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 2-ethyl-6-methoxypyridin-3-ylboronic acid, andstirring the reaction mixture for 1 h at 100° C. The crude product waspurified by flash chromatography (hexane/EtOAc, 1:3) and subsequenttrituration in Et₂O/hexane (1:4). t_(R): 1.43 min (LC-MS 2); ESI-MS:549.3/551.3 [M+H]⁺ (LC-MS 2); R_(f): 0.40 (hexane/EtOAc, 1:3).

Example 482-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 2 equivalents of intermediate U, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 30 min at 100° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5) and subsequent trituration in Et₂O.t_(R): 1.15 min (LC-MS 2); ESI-MS: 537.3/539.3 [M+H]⁺ (LC-MS 2); R_(f):0.12 (CH₂Cl₂/MeOH, 95:5).

Example 493-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-ethyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using 1.8 equivalents of intermediate V, and 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex. The crude product waspurified by flash chromatography (hexane/EtOAc, 1:1) and subsequenttrituration in Et₂O. t_(R): 1.30/1.33 min (LC-MS 2); ESI-MS: 543.3/545.2[M+H]⁺ (LC-MS 2); R_(f): 0.13 (hexane/EtOAc, 1:1).

Example 505-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 2 equivalents of intermediateT, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 3 h at 100° C. After flash chromatography(CH₂Cl₂/MeOH, 95:5) of the crude product and subsequent trituration inEt₂O, the resulting material was further purified by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 30 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.19 min (LC-MS 2); ESI-MS: 508.2/510.2 [M+H]⁺ (LC-MS 2); R_(f):0.26 (CH₂Cl₂/MeOH, 95:5).

Example 515-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-4-methoxy-pyrimidin-5-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 1.5 equivalents of intermediate X, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 2 h at 110° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration of theresulting material in Et₂O/hexane (1:1). t_(R): 1.22/1.25 min (LC-MS 2);ESI-MS: 595.3/597.3 [M+H]⁺ (LC-MS 2); R_(f): 0.14 (CH₂Cl₂/MeOH, 95:5).

Example 525-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(2-hydroxy-ethylamino)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 1.5 equivalents of intermediate Y, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 1 h at 110° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 30 min; A=0.1% TFA in water, B=CH₃CN) and trituration of theresulting material in Et₂O/hexane (1:1). t_(R): 1.15/1.18 min (LC-MS 2);ESI-MS: 581.3/583.2 [M+H]⁺ (LC-MS 2); R_(f): 0.15 (CH₂Cl₂/MeOH,92.5:7.5).

Example 534-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB, 2 equivalents of intermediateU, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 0.96 min (LC-MS 2); ESI-MS: 518.2/520.2 [M+H]⁺ (LC-MS 2);R_(f): 0.28 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 544-[5-(3-Chloro-2-fluoro-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB, 2 equivalents of intermediateZ, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5) followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 20 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.03 min (LC-MS 2); ESI-MS: 532.3/534.3 [M+H]⁺ (LC-MS 2); R_(f):0.23 (CH₂Cl₂/MeOH, 95:5).

Example 554-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo-[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB, 2 equivalents of intermediateW, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.14 min (LC-MS 2); ESI-MS: 546.3/548.3 [M+H]⁺ (LC-MS 2); R_(f):0.39 (CH₂Cl₂/MeOH, 95:5).

Example 564-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AC, 2 equivalents of intermediateU, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 0.99 min(LC-MS 2); ESI-MS: 518.3/520.3 [M+H]⁺ (LC-MS 2); R_(f): 0.24(CH₂Cl₂/MeOH, 92.5:7.5).

Example 574-[5-(3-Chloro-4-fluoro-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AC, 2 equivalents of intermediateZ, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 20 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 1.06 min (LC-MS 2); ESI-MS: 532.3/534.3 [M+H]⁺ (LC-MS 2);R_(f): 0.31 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 584-[5-(3-Chloro-4-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo-[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AC, 2 equivalents of intermediateW, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-70%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.16 min (LC-MS 2); ESI-MS: 546.3/548.3 [M+H]⁺ (LC-MS 2); R_(f):0.30 (CH₂Cl₂/MeOH, 95:5).

Example 595-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-3-methyl-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of intermediateAD, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration in Et₂O.t_(R): 1.15 min (LC-MS 2); ESI-MS: 593.3/595.3 [M+H]⁺ (LC-MS 2); R_(f):0.11 (CH₂Cl₂/MeOH, 95:5).

Example 605-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(3-hydroxy-3-methyl-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 1.5 equivalents of intermediate AD, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 30 min at 110° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.17/1.19 min (LC-MS2); ESI-MS: 607.3/609.3 [M+H]⁺ (LC-MS 2); R_(f): 0.09 (CH₂Cl₂/MeOH,95:5).

Example 615-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate E, 1.5 equivalents of intermediateAE, 0.15 equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring thereaction mixture for 30 min at 110° C. The crude product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparativeHPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient30-60% B in 20 min; A=0.1% TFA in water, B=CH₃CN) and trituration inEt₂O. t_(R): 1.10 min (LC-MS 2); ESI-MS: 579.2/581.2 [M+H]⁺ (LC-MS 2);R_(f): 0.14 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 625-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using 1.5 equivalents of intermediate AE, 0.15equivalents of PdCl₂(dppf)-CH₂Cl₂ complex, and stirring the reactionmixture for 30 min at 110° C. The crude product was purified by flashchromatography (CH₂Cl₂/MeOH, 92.5:7.5), followed by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 20-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.14-1.16 min (LC-MS2); ESI-MS: 593.3/595.3 [M+H]⁺ (LC-MS 2); R_(f): 0.17 (CH₂Cl₂/MeOH,92.5:7:5).

Example 63 2-(4-Aminomethyl-2-methoxy-phenyl-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was obtained in analogy to the procedure describedfor the preparation of example 16 using the product from example 26 asstarting material. t_(R): 0.97 min (LC-MS 2); ESI-MS: 535.2/537.2 [M+H]⁺(LC-MS 2).

Example 645-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The product from step 64.1 (160 mg, 0.23 mmol) was dissolved in DMF (5mL) and HATU (98 mg, 0.26 mmol) and NMM (77 μL, 0.70 mmol) were added.The reaction mixture was stirred for 12 h at rt and then heated to 80°C. for 2 h. It was allowed to cool and concentrated. The residual crudematerial was purified by preparative HPLC (column xBridge 30×100 mm;0.08% TFA-water/acetonitrile; gradient acetonitrile 5-100%). t_(R): 1.29min (LC-MS 2); ESI-MS: 524.2/526.2 [M+H]⁺ (LC-MS 2).

Step 64.15-[(3-Chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid

The product from step 64.2 (280 mg, 0.50 mmol) was dissolved in dioxane(4 mL) and H₂O (1 mL). LiOH monohydrate (32 mg, 0.75 mmol) was added andthe reaction mixture stirred at 60° C. for 3 h. All volatiles wereremoved in vacuum and the residual crude material directly submitted tothe next step.

Step 64.25-[3-Chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid methyl ester

Intermediate D (620 mg, 1.45 mmol) was dissolved in DCM (15 mL). TEA(366 mg, 0.5 mL, 3.61 mmol) and MsCl (331 mg, 2.90 mmol) were added andthe reaction mixture was stirred at rt for 6 h. All volatiles wereremoved under reduced pressure and the residual crude mesylatere-dissolved in DCM (10 mL). 3-Chloro-2-fluoro aniline (310 mg, 2.13mmol) was added and stirring continued at rt for 16 h. The solvent wasevaporated under reduced pressure. EtOAc (10 mL) and TEA (0.5 mL) wereadded and the mixture stirred for 5 min at rt. The white precipitate wasfiltered off and the filtrate concentrated to give the crude productwhich was purified by flash chromatography (heptanes/EtOAc, 100:0→1:1)to give the title compound. t_(R): 1.42 min (LC-MS 2); ESI-MS:556.3/558.3 [M+H]⁺ (LC-MS 2).

Example 655-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate J and 2,4-dimethoxypyrimidin-5-ylboronic acid. t_(R): 0.95 min (LC-MS 2); ESI-MS: 555.4/557.3 [M+H]⁺(LC-MS 2).

Example 665-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate J and intermediate W. t_(R): 1.05 min(LC-MS 2); ESI-MS: 568.3/570.4 [M+H]⁺ (LC-MS 2).

Example 672-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate J and intermediate U. t_(R): 0.84 min(LC-MS 2); ESI-MS: 540.3/542.3 [M+H]⁺ (LC-MS 2).

Example 683-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate J and intermediate M. t_(R): 0.92 min(LC-MS 2); ESI-MS: 594.2/596.4 [M+H]⁺ (LC-MS 2).

Example 695-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate G and intermediate O. t_(R): 1.11 min(LC-MS 2); ESI-MS: 623.2/625.2 [M+H]⁺ (LC-MS 2).

Example 703-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate G and intermediate M. t_(R): 1.12 min(LC-MS 2); ESI-MS: 581.2/583.2 [M+H]⁺ (LC-MS 2).

Example 716-(4-Chloro-2-methyl-phenyl)-5-(4-chloro-pyrimidin-2-yl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate 1 and 2-methoxy-phenylboronic acid.t_(R): 1.37/1.40 min (LC-MS 2); ESI-MS: 507.2/509.3 [M+H]⁺ (LC-MS 2).

Example 726-(4-Chloro-phenyl)-5-(5-chloro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AF and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.11 min (LC-MS 2); ESI-MS: 525.2/527.3 [M+H]⁺(LC-MS 2).

Example 733-[5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethylbenzamide

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate AG and intermediate M, except usingPd(PPh₃)₂Cl₂ (0.1 equiv) and Na₂CO₃ (3.0 equiv) instead of K₃PO₄. t_(R):1.16 min (LC-MS 2); ESI-MS: 563.2/565.2 [M+H]⁺ (LC-MS 2).

Example 744-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-NN-dimethyl benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate F and intermediate AH. t_(R): 1.17/1.19min (LC-MS 2); ESI-MS: 591.3/593.3 [M+H]⁺ (LC-MS 2).

Example 75(S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 7 (column: Chiralcel OD 20 μM, 5×50cm, flow 80 mL/min, heptanes/EtOH 65:35). t_(R): 5.80 min; >99% ee(Column: Chiralcel OD H 5 μM 4.6×250 mm (DIACEL). Flow 1.0 mL/min.heptanes/EtOH 65:35. Detection: UV 210 nm). t_(R): 1.22/1.26 min (LC-MS2); ESI-MS: 552.3/554.3 [M+H]⁺ (LC-MS 2); ¹H NMR (DMSO-d₆, 400 MHz) δppm 8.54/8.52 (s, 1H; rotamers), 7.95/7.88 (d, 1H; rotamers), 7.26-7.23(m, 3H), 7.16 (d, 1H), 7.03 (d, 1H), 6.87/6.67 (s, 1H; rotamers), 4.16(sep, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 2.34/2.30 (s, 3H; rotamers);1.92/1.90 (s, 3H; rotamers), 1.30-12.6 (m, 3H; rotamers), 0.68/0.59 (d,3H; rotamers).

Example 76(R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6,-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 7 (column: Chiralcel OD 20 δ M, 5×50cm, flow 80 mL/min, heptanes/EtOH 65:35). t_(R): 12.46 min (Column:Chiralcel OD H 5 δ M 4.6×250 mm (DIACEL). Flow 1.0 mL/min. heptanes/EtOH65:35. Detection: UV 210 nM); >99% ee (Column: Chiralcel OD H 5 δ M4.6×250 mm (DIACEL). Flow 1.0 mL/min. heptanes/EtOH 65:35. Detection: UV210 nm). t_(R): 1.22/1.26 min (LC-MS 2); ESI-MS: 552.3/554.3 [M+H]⁺(LC-MS2); ¹H NMR (DMSO-d₆ 400 MHz) δ ppm 8.54/8.52 (s, 1H; rotamers),7.95/7.88 (d, 1H; rotamers), 7.26-7.23 (m, 3H), 7.16 (d, 1H), 7.03 (d,1H), 6.87/6.67 (s, 1H; rotamers), 4.16 (sep, 1H), 4.00 (s, 3H), 3.96 (s,3H), 2.34/2.30 (s, 3H; rotamers); 1.92/1.90 (s, 3H; rotamers), 1.30-12.6(m, 3H; rotamers), 0.68/0.59 (d, 3H; rotamers).

Example 774-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate H and 2-methoxy-phenylboronic acid.t_(R): 1.12 min (LC-MS 2); ESI-MS: 497.3/499.3 [M+H]⁺ (LC-MS 2).

Example 784-[5-(5-Chloro-2-methyl-phenyl)-2-(2-hydroxy-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate H and 2-hydroxyphenyl boronic acidpinacol ester. t_(R): 1.06 min (LC-MS 2); ESI-MS: 483.3/485.3 [M+H]⁺(LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 10.05 (s, 1H), 7.79 (m, 2H),7.50 (m, 2H), 7.33 (m, 3H), 7.16 (m, 2H), 6.96 (m, 2H), 6.68 (s, 1H),4.16 (m, 1H), 1.92 (s, 3H), 3.77 (m, 3H), 0.51 (m, 3H).

Example 794-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AB and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.03 min (LC-MS 2); ESI-MS: 533.2 [M+H]⁺ (LC-MS 2).

Example 804-[5-(3-Chloro-4-fluoro-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AC and 2-methoxy-phenylboronic acid.t_(R): 1.11 min (LC-MS 2); ESI-MS: 501.3/503.5 [M+H]⁺ (LC-MS 2).

Example 813-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AC and intermediate M. t_(R): 1.00 min(LC-MS 2); ESI-MS: 572.3/574.3 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400MHz) δ ppm 7.83 (m, 3H), 7.62 (m, 3H), 7.53 (m, 1H), 7.45 (m, 1H), 7.34(m, 1H), 7.23 (m, 1H), 6.86 (s, 1H), 4.04 (m, 1H), 3.60 (s, 3H), 2.95(s, 6H), 1.37 (m, 3H), 0.42 (m, 3H).

Example 824-[5-(3-Chloro-4-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AC and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.04 min (LC-MS 2); ESI-MS: 533.3/535.3 [M+H]⁺(LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.46 (s, 1H), 7.83 (m, 3H),7.63 (m, 2H), 7.52 (m, 1H), 7.34 (m, 1H), 6.86 (s, 1H), 4.10 (s, 1H),3.96 (s, 3H), 3.91 (s, 3H), 1.36 (m, 3H), 0.45 (m, 3H).

Example 836-(4-Chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AI and 2-methoxy-phenylboronic acid.t_(R): 0.98 min (LC-MS 2); ESI-MS: 493.3 [M+H]⁺ (LC-MS 2).

Example 846-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-(1-methyl-6-oxo-piperidin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate AI and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 0.89 min (LC-MS 2); ESI-MS: 525.4/527.2 [M+H]⁺(LC-MS 2).

Example 855-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate AK and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.24 min (LC-MS 2); ESI-MS: 554.2/556.2 [M+H]⁺(LC-MS 2).

Example 865-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate AL and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.27 min (LC-MS 2); ESI-MS: 550.0/552.0/552.7[M+H]⁺ (LC-MS 2).

Example 874-[5-(3-Chloro-4-fluoro-phenyl)-3-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate AM and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.07 min (LC-MS 2); ESI-MS: 545.3/547.4 [M+H]⁺(LC-MS 2).

Example 885-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-2-(2,4-dimethoxypyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 using intermediate AN and 2,4-dimethoxy-pyrimidin-5-ylboronic acid. t_(R): 1.21 min (LC-MS 2); ESI-MS: 540.2/542.2 [M+H]⁺(LC-MS 2).

Example 89(S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 18 (column: Chiralpak IA 250 mm×30mm×5 μM, flow 80 mL/min, isochratic 100% EtOH). t_(R): 1.75 min (Column:Chiralpak IC 4.6×250 mm×20 μM. Flow: 1 mL/min. Mobile phase: EtOH/MeOH:50:50).

Example 90(R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazole-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 18 (column: Chiralpak IA 250 mm×30mm×5 μM, flow 80 mL/min, isochratic 100% EtOH). t_(R): 2.65 min (Column:Chiralpak IC 4.6×250 mm×20 μM. Flow: 1 mL/min. Mobile phase: EtOH/MeOH:50:50).

Example 916-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 91.1 and intermediate W.After completion, the water phase was removed with a pipette. Thereaction mixture was diluted in MeOH then filtered through aStratoSphere SPE cartridge (PL-Thiol MP SPE) and washed with MeOH. Theresidue was purified by flash chromatography (CH₂Cl₂/MeOH, 100:0→90:10).The residue was then purified by preparative HPLC (Column: Sunfire C18,30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1%TFA in water, B=CH₃CN). t_(R): 1.07 min (LC-MS 2); ESI-MS: 521.2/523.2[M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.20 (s, 1H), 7.44 (m,2H), 7.36 (m, 2H), 6.27 (s, 1H), 5.86 (s, 1H), 4.09 (m, 1H), 3.88 (s,3H), 3.42 (s, 3H), 3.16 (s, 6H), 2.03 (s, 3H), 1.29 (m, 3H), 0.51 (m,3H).

Step 91.12-Bromo-6-(4-chloro-phenyl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 91.2 (315 mg, 0.675 mmol) inCH₂Cl₂ (3.3 mL) was added 1-chloro-N,N,2-trimethyl-1-propenylamine (107μl, 0.810 mmol) at 0° C. and the mixture was stirred overnight at rt.The reaction mixture was extracted with EtOAc. The organic layers werewashed with water then brine, dried (Na₂SO₄), filtered and concentrated.The product was used without further purification. t_(R): 0.97 min(LC-MS 2); ESI-MS: 448.1/450.1/452.0 [M+H]⁺ (LC-MS 2).

Step 91.22-Bromo-5-[(4-chloro-phenyl)-(2,5-dimethyl-2H-pyrazol-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 91.3. t_(R): 0.90 min (LC-MS3); ESI-MS: 466.1/468.1/470.2 [M+H]⁺ (LC-MS 3).

Step 91.32-Bromo-5-[(4-chloro-phenyl)-(2,5-dimethyl-2H-pyrazol-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using 5-amino-1,3-dimethylpyrazole. The crude productwas purified by flash chromatography (CH₂Cl₂/EtOAc, 100:0→80:20). t_(R):1.10 min (LC-MS 2); ESI-MS: 494.1/496.1/498.1 [M+H]⁺ (LC-MS 2);R_(f)=0.17 (CH₂Cl₂/EtOAc, 3:2).

Example 926-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 91 but using 2,4-dimethylpyrimidine-5-boronic acid. t_(R):0.97 min (LC-MS 2); ESI-MS: 508.2/510.3 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.48 (s, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 6.30(s, 1H), 5.87 (s, 1H), 5.75 (s, 1H), 4.13 (m, 1H), 3.96 (s, 3H), 3.93(s, 3H), 3.43 (s, 3H), 2.03 (s, 3H), 1.30 (m, 3H), 0.52 (m, 3H).

Example 93{4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the products from steps 93.1 and 93.4. Thereaction was stirred at 80° C. for 1.5 h. The reaction mixture waspoured into a saturated aqueous NaHCO₃ solution and extracted withEtOAc. The organic layers were washed with brine, dried (Na₂SO₄),filtered and concentrated. The crude product was purified by flashchromatography (heptane/CH₂Cl₂/EtOAc, 90:9:1→0:95:5) to give the titlecompound as a beige foam. t_(R): 1.16 min (LC-MS 2); ESI-MS: 564.1/566.1[M+H]⁺ (LC-MS 2).

Step 93.12-Bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 93.2. The reaction wasperformed in 30 min. The reaction mixture was poured into a saturatedaqueous NaHCO₃ solution and extracted with EtOAc. The organic layerswere washed with a saturated aqueous NaHCO₃ solution and brine, dried(Na₂SO₄), filtered and concentrated. The residue was triturated inDiisopropylether to give the title compound as a white solid. t_(R):1.23 min (LC-MS 2); ESI-MS: 496.0/498.0/500.0 [M+H]⁺ (LC-MS 2).

Step 93.22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product was step 93.3. The mixture was stirredat rt for 30 min. An aqueous citric acic (1M) solution was added untilpH=4 and the mixture was extracted with CH₂Cl₂. The organic layers weredried (Na₂SO₄), filtered and concentrated. The product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5) to give the title compound aswhite solid. t_(R): 1.26 min (LC-MS 2); ESI-MS: 514.0/516.0/518.0 [M+H]⁺(LC-MS 2).

Step 93.32-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate C and 3-chloro-2-fluoroaniline. Thereaction was stirred at rt for 1.5 h. The reaction mixture was dilutedwith H₂O and extracted. The organic layers were washed with a saturatedaqueous NaHCO₃ solution, dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by flash chromatography (hexane/EtOAc, 90:1→65:35).The residue was then triturated in CH₂Cl₂ to give the title compound aswhite foam. t_(R): 1.45 min (LC-MS 2); ESI-MS: 542.0/544.0/546.0 [M+H]⁺(LC-MS 2).

Step 93.4[5-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-acetonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 93.5. The reactionmixture was dissolved in toluene, filtered over Hyflo and the motherliquor was concentrated to give the title compound (60% purity). ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm: 8.33 (s, 1H), 7.92 (s, 1H), 4.10 (s, 2H), 3.84(s, 3H), 1.27 (s, 6H), 1.14 (s, 6H).

Step 93.5 (4-Bromo-5-methoxy-pyridin-2-yl)-acetonitrile

A suspension of the product from step 93.6 (1.2 g, 4.3 mmol), KCN (417mg, 6.4 mmol) and aliquat 336 (35 mg, 0.085 mmol) in H₂O was stirred at50° C. for 2 h. The reaction mixture was dissolved in CH₂Cl₂, extractedwith a saturated aqueous NaHCO₃ solution, washed with brine, dried(Na₂SO₄), filtered and concentrated. The crude product was purified byflash chromatography (hexane/EtOAc, 100:0→1:1). t_(R): 3.83 min (HPLC1).

Step 93.6 4-Bromo-2-bromomethyl-5-methoxy-pyridine

A solution of the product from step 93.7 (1.9 g, 9.4 mmol), NBS (1.8 g,9.9 mmol), AIBN (15 mg, 0.094 mmol) and benzoyl peroxide (23 mg, 0.094mmol) in CCl₄ (2 mL) was stirred at rt for 18 h. The reaction mixturewas dissolved in EtOAc and extracted with a saturated aqueous NaHCO₃solution, washed with brine, dried (Na₂SO₄), filtered and concentrated.The crude product was purified by flash chromatography (hexane/EtOAc,100:0→70:30). t_(R): 0.90 min (LC-MS 2); ESI-MS: 279.9/281.9/283.9[M+H]⁺ (LC-MS 2).

Step 93.7 4-Bromo-5-methoxy-2-methyl-pyridine

To a solution of the product from step 93.8 (150 mg, 0.7 mmol) in CHCl₃(2 mL) at 10° C. was added dropwise PBr₃ (78 μL, 0.826 mmol). Themixture was stirred at rt for 4 h, then at 50° C. for 1 h. The reactionmixture was dissolved in CH₂Cl₂ and extracted with a saturated aqueousNaHCO₃ solution, washed with brine, dried (Na₂SO₄), filtered andconcentrated. The product was crystallised (CH₂Cl₂/TBME). t_(R): 0.69min (LC-MS 2); ESI-MS: 202.0/204.0 [M+H]⁺ (LC-MS 2).

Step 93.8 4-Bromo-5-methoxy-2-methyl-pyridine 1-oxide

The product from step 93.9 (1.9 g, 10.3 mmol) and acetyl bromide (22.9mL, 310 mmol) was added to AcOH (40 mL) and the reaction was stirred at80° C. for 1 h. The mixture was concentrated (1/3) and a solution ofNaOH was added. The resulting mixture was extracted with EtOAc, washedwith brine, dried (Na₂SO₄), filtered and concentrated. The product wascrystallised (EtOAc/TBME). t_(R): 0.54 min (LC-MS 2); ESI-MS:218.1/220.1 [M+H]⁺ (LC-MS 2).

Step 93.9 5-Methoxy-2-methyl-4-nitro-pyridine-1-oxide

5-methoxy-2-methylpyridine-1-oxide (6 g, 43.1 mmol) and nitric acid(18.4 mL, 431 mmol, 1.48 g/mL) was added to AcOH (50 mL) and thereaction was stirred at 90° C. for 6 h. The mixture was concentrated(1/4) and neutralized at 0° C. was addition of ammonium hydroxide. Themixture was extracted with EtOAc, washed with brine and water, dried(Na₂SO₄), filtered and concentrated. The product crystallised duringconcentration. t_(R): 0.50 min (LC-MS 2); ESI-MS: 185.1 [M+H]⁺ (LC-MS2).

Example 944-[6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 94.1 and intermediate W.The residue was purified by preparative HPLC (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile20-40% in 16 min) to give the title compound. t_(R): 1.01 min (LC-MS 2);ESI-MS: 560.2 [M+H]⁺ (LC-MS 2).

Step 94.14-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzamide

A solution of the product from step 94.2 (1.4 g, 3.0 mmol) inconcentrated H₂SO₄ (31.8 mL, 596 mmol) was stirred at rt for 20 h. Thereaction mixture was dissolved in EtOAc and H₂O, neutralized with asaturated aqueous NaHCO₃ solution and the phases were separated. Theaqueous phase was washed with EtOAc. The organic layers were dried(Na₂SO₄), filtered and concentrated. t_(R): 0.93 min (LC-MS 2); ESI-MS:487.0/489.1 [M+H]⁺ (LC-MS 2).

Step 94.24-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 94.3. The product wastriturated in EtOAc and the resulting suspension was filtered to givethe title compound. t_(R): 1.12 min (LC-MS 2); ESI-MS: 469.2/471.2[M+H]⁺ (LC-MS 2).

Step 94.32-Bromo-5-[(4-chloro-phenyl)-(4-cyano-2-methyl-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 94.4. t_(R): 1.13 min (LC-MS2); ESI-MS: 487.2/489.2 [M+H]⁺ (LC-MS 2).

Step 94.42-Bromo-5-[(4-chloro-phenyl)-(4-cyano-2-methyl-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 4-amino-3-methylbenzonitrile.The reaction mixture was stirred at rt for 20 h. The mixture wasextracted with HCl 1M and with a saturated aqueous NaHCO₃ solution. Theorganic layers were dried (Na₂SO₄), filtered and concentrated. Theproduct was triturated in Et₂O, the suspension was filtered and thesolid was dried in HV. t_(R): 1.30 min (LC-MS 2); ESI-MS: 515.2/517.1[M+H]⁺ (LC-MS 2).

Example 954-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 94.1 and2,4-dimethylpyrimidine-5-boronic acid. The residue was purified by SFCchromatography (Column 2-EP, 250×30 mm, 5 μm, flow 100 mL/min, grad25-30% over 6 min) to give the title compound. t_(R): 0.92 min (LC-MS2); ESI-MS: 547.2/549.3 [M+H]⁺ (LC-MS 2).

Example 965-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-2-oxo-1,2-dihydro-pyrimidin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 96.1 (20 mg, 0.04 mmol) indioxane/H₂O (800 μl, 1:1) was added K₂CO₃ (9.1 mg, 0.07 mmol) and DABCO(2.0 mg, 0.02 mmol) and the mixture was stirred at 70° C. for 16 h.EtOAc and H₂O were added and the phases were separated. The organiclayers were dried (Na₂SO₄), filtered and concentrated. The residue waspurified by SFC chromatography (Column 2-EP, 250×30 mm, 5 μm, flow 100mL/min, grad 18-23% over 6 min) to give the title compound. t_(R): 0.98min (LC-MS 2); ESI-MS: 528.2/530.2 [M+H]⁺ (LC-MS 2).

Step 96.15-(3-Chloro-2-fluoro-phenyl)-2-(2-chloro-5-methoxy-pyrimidin-4-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of intermediate G (300 mg, 0.6 mmol) in dioxane (6.4 mL)was added Pd(PPh₃)₄ (144 mg, 0.1 mmol), then the product from step 96.2(487 mg, 1.9 mmol) and the reaction mixture was stirred at 70° C. for 1h and at 80° C. for 1 h more. The mixture was diluted with EtOAc andextracted with H₂O. The organic layers were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 50-70% in 16 min) to give the title compound. t_(R): 1.22min (LC-MS 2); ESI-MS: 546.1 [M+H]⁺ (LC-MS 2).

Step 96.2 (2-Chloro-5-methoxypyrimidin-4-yl)zinc

A solution of dry ZnCl (400 mg, 2.9 mmol) and2,2,6,6-tetramethylpiperidinylmagnesiumchloride lithium chloridecomplex, 1M in THF (5.5 mL, 5.53 mmol) was stirred at RT for 16 h. Then2-chloro-5-methoxypyrimidine (800 mg, 5.53 mmol) was added dropwise andthe mixture was stirred at rt for 1 h. The product was used as a stocksolution for the next step.

Example 975-(4-Amino-cyclohexyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

A solution of the product from step 97.1 (158 mg, 0.2 mmol) and TFA (359μl, 4.65 mmol) was stirred at rt for 1 h. At 0° C., the pH was adjustedto 8 with a saturated aqueous NaHCO₃ solution. The mixture was extractedwith EtOAc. The organic layers were washed with brine, dried (MgSO₄),filtered and concentrated. The product was purified by preparative HPLC(Column Atlantis, Flow: 23 mL/min. Gradient 5-100% B in 7 min; A=0.1%TFA in water, B=acetonitrile) to provide the title compound. t_(R): 0.76min (LC-MS 2); ESI-MS: 511.3/513.2 [M+H]⁺ (LC-MS 2).

Step 97.1{4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexyl}-carbamicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 97.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction mixture wasdiluted with a saturated aqueous NaHCO₃ solution, and was extracted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), filtered,and concentrated. The residue was purified by flash chromatography(hexane/EtOAc, 75:25→0:100). t_(R): 1.17 min (LC-MS 2); ESI-MS:611.5/613.5 [M+H]⁺ (LC-MS 2).

Step 97.2{4-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexyl}-carbamicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product was step 97.3. The crude waspurified by flash chromatography (hexane/EtOAc, 70:30→0:100) to affordthe title compound. t_(R): 1.19 min (LC-MS 2); ESI-MS: 551.2/553.3[M+H]⁺ (LC-MS 2).

Step 97.32-Bromo-5-[(4-tert-butoxycarbonylamino-cyclohexylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 97.4. t_(R): 0.91 min (LC-MS2); ESI-MS: 569.3/571.3 [M+H]⁺ (LC-MS 2).

Step 97.42-Bromo-5-[(4-tert-butoxycarbonylamino-cyclohexylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B andtrans-1-Boc-amino-1,4-cyclohexanediamine. The reaction mixture wasstirred at 50° C. for 19 h. The reaction mixture was diluted inEtOAc/water and the phases were separated. The organic extracts weredried (Na₂SO₄) and concentrated. The crude was purified by flashchromatography (hexane/EtOAc, 80:20→0:100) to afford the title compound.t_(R): 1.33 min (LC-MS 2); ESI-MS: 597.3/599.5 [M+H]⁺ (LC-MS 2).

Example 984-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexanecarboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 98.1. The residue waspurified by flash chromatography (CH₂Cl₂/MeOH, 97:3→8:2). t_(R): 0.96min (LC-MS 2); ESI-MS: 540.3/542.3 [M+H]⁺ (LC-MS 2).

Step 98.14-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexanecarboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 98.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction mixture wasdiluted with a saturated aqueous NaHCO₃ solution, and was extracted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), filtered,and concentrated. The residue was purified by flash chromatography(hexane/EtOAc, 80:20→0:100). t_(R): 1.28 min (LC-MS 2); ESI-MS: 596.4[M+H]⁺ (LC-MS 2).

Step 98.24-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo-[3,4-d]imidazol-5-yl]-cyclohexanecarboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product was step 98.3. The crude waspurified by flash chromatography (hexane/EtOAc, 70:30→0:100) to affordthe title compound. t_(R): 1.30 min (LC-MS 2); ESI-MS: 536.3/538.3[M+H]⁺ (LC-MS 2).

Step 98.32-Bromo-5-[(4-tert-butoxycarbonyl-cyclohexylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product was step 98.4. The mixture was stirredat rt for 3 h. t_(R): 0.98 min (LC-MS 2); ESI-MS: 554.3/556.3 [M+H]⁺(LC-MS 2).

Step 98.42-Bromo-5-[(4-tert-butoxycarbonyl-cyclohexylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 98.5. The reaction wasperformed at 45° C. The resulting mixture was diluted in H₂O and asaturated aqueous NaHCO₃ solution and extracted with CH₂Cl₂. The organiclayers were washed with brine, dried (MgSO₄), filtered and concentrated.The crude product was purified by flash chromatography (heptane/EtOAc,80:20→0:100). t_(R): 1.48 min (LC-MS 2); ESI-MS: 584.3/584.3 [M+H]⁺(LC-MS 2).

Step 98.5 4-Amino-cyclohexanecarboxylic acid tert-butyl ester

A mixture of the compound prepared in step 98.6 (1.3 g, 3.4 mmol) andPd/C 10% (113 mg) in MeOH (25 mL) was stirred for 1 h at rt, under ahydrogen atmosphere. The reaction mixture was filtered through a pad ofcelite, washed with THF and MeOH and concentrated. t_(R): 0.14 min(LC-MS 2); ESI-MS: 200.2 [M+H]⁺ (LC-MS 2).

Step 98.6 4-Benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butylester

To a suspension of (1R,4R)-4-benzoylcarbonylamino-cyclohexanecarboxylicacid (1 g, 3.6 mmol) in toluene (20 mL) at 40° C. was addeddi-tert-butoxymethyl-dimethylamine (8.0 mL, 33.5 mmol) and the mixturewas stirred at 95° C. for 10 h. The reaction mixture was extracted witha mixture of saturated aqueous NaHCO₃ solution and H₂O (1:1). Theorganic layer was washed with a saturated aqueous NaHCO₃ solution andbrine, dried (MgSO₄), filtered and concentrated. The aqueous layer waswashed with EtOAc. The resulting organic layer was washed with brine,dried (MgSO₄), filtered and concentrated. The product was used withoutfurther purification for the next step. t_(R): 5.46 min (HPLC 2);ESI-MS: 332.1 [M−H]⁻ (MS 1).

Example 99N-{4-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo-[3,4-d]imidazol-5-yl]-cyclohexyl}-acetamide

To a solution of the product from example 97 (60 mg, 0.2 mmol) and TEA(33 μL, 0.2 mmol) was added acetic anhydride (13 μL, 0.1 mmol) and themixture was stirred at rt for 30 in. The mixture was diluted in H₂O andEtOAc. The phases were separated and the organic layers were dried(MgSO₄), filtered and concentrated. The product was purified by flashchromatography (CH₂Cl₂/MeOH, 97:3→80:20) to provide the title compound.t_(R): 0.91 min (LC-MS 2); ESI-MS: 553.3 [M+H]⁺ (LC-MS 2).

Example 1004-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 100.1 and intermediate W.The reaction was performed at 110° C. The product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5), then the residue was triturated inEt₂O to provide the title compound. t_(R): 0.97 min (LC-MS 2); ESI-MS:559.4/561.4 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d, 400 MHz) δ ppm 8.19 (s,1H), 7.90 (d, 1H), 7.86-7.78 (m, 2H), 7.58-7.47 (m, 3H), 6.76 (s, 1H),4.18-4.00 (m, 1H), 3.86 (s, 3H), 3.45-3.36 (m, 3H), 3.16 (s, 6H), 1.31(d, 3H), 0.46 (d, 3H).

Step 100.14-[2-Bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 100.2. t_(R): 0.87min (LC-MS 2); ESI-MS: 486.1/488.1 [M+H]⁺ (LC-MS 2).

Step 100.22-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 100.3. After extraction, theresidue was triturated in EtOAc to afford the title compound. t_(R):0.89 min (LC-MS 2); ESI-MS: 504.2/506.2 [M+H]⁺ (LC-MS 2).

Step 100.32-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate H3 and the product from step 100.4.The reaction mixture was stirred at rt for 72 h. After the flashchromatography, the product was triturated in Et₂O to afford the titlecompound. t_(R): 1.09 min (LC-MS 2); ESI-MS: 532.3/534.3 [M+H]⁺ (LC-MS2).

Step 100.4 3-Amino-5-chloro-1-methyl-1H-pyridin-2-one

A mixture of the compound prepared in step 100.5 (1.7 g, 9 mmol) andRaney nickel (300 Mg) in MeOH (100 mL) and THF (30 mL) was stirred for16.5 h at rt, under a hydrogen atmosphere. The reaction mixture wasfiltered through a pad of celite, and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 30:70) to afford thetitle compound. t_(R): 0.52 min (LC-MS 2); ESI-MS: 159.1/161.1 [M+H]⁺(LC-MS 2), R_(f)=0.22 (hexane/EtOAc, 3:7).

Step 100.5 5-Chloro-1-methyl-3-nitro-1H-pyridin-2-one

A mixture of NaH (577 mg, 14.4 mmol) and5-chloro-2-hydroxy-3-nitropyridine (2.1 g, 12.0 mmol) in DMF (21 mL) wasstirred for 1 h at 5° C. Methyl iodide (1.1 mL, 18.0 mmol) was added.The resulting mixture was allowed to warm to rt, stirred overnight,cooled to 0° C., quenched by addition of water, and extracted withEtOAc. The organic layer was dried (Na₂SO₄), filtered, and concentrated.The residue was used without further purification. t_(R): 0.61 min(LC-MS 2); ESI-MS: 189.1/191.1 [M+H]⁺ (LC-MS 2).

Example 1015-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 101.1 and2,4-dimethoxypyrimidin.5.ylboronic acid. The reaction was performed at110° C. The residue was purified by flash chromatography (CH₂Cl₂/MeOH,95:5) then was purified by preparative HPLC (Column: Sunfire C18, 30×100mm, 5 μm. Flow: 30 mL/min. Gradient 30-80% B in 20 min; A=0.1% TFA inwater, B=CH₃CN) to afford the title compound. t_(R): 1.05 min (LC-MS 2);ESI-MS: 555.3/557.2 [M+H]⁺ (LC-MS 2); R_(f)=0.19 (CH₂Cl₂/MeOH, 95:5).

Step 101.12-Bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 101.2. Afterextraction, the residue was triturated in EtOAc to afford the titlecompound. t_(R): 1.07 min (LC-MS 2); ESI-MS: 495.0/497.1/499.0 [M+H]⁺(LC-MS 2).

Step 101.22-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-Pyridin-3-ylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 101.3. The residue wastriturated in Et₂O to afford the title compound. t_(R): 1.05 min (LC-MS2); ESI-MS: 513.2/515.1/517.1 [M+H]⁺ (LC-MS 2).

Step 101.32-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 100.4. After extraction, theresidue was triturated in EtOAc to afford the title compound. t_(R):1.27 min (LC-MS 2); ESI-MS: 541.1/543.1/545.1 [M+H]⁺ (LC-MS 2).

Example 102(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 101. (Column: Chiralpak AD, 76.5×390mm. Flow 120 mL/min. hexane/EtOH/MeOH 50:25:25). t_(R): 5.5 min (Column:Chiralpak AD, 4.6×250 mm. Flow 1 mL/min. hexane/EtOH/MeOH 50:25:25);¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.49 (s, 1H), 7.92 (d, 1H), 7.51 (d,1H), 7.41 (m, 2H), 7.33 (m, 2H), 6.71 (s, 1H), 4.10 (m, 1H), 3.97 (s,3H), 3.93 (s, 3H), 3.43 (s, 3H), 1.33 (d, 3H), 0.51 (d, 3H).

Example 103(R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 101. (Column: Chiralpak AD, 76.5×390mm. Flow 120 mL/min. hexane/EtOH/MeOH 50:25:25). t_(R): 10.9 min(Column: Chiralpak AD, 4.6×250 mm. Flow 1 mL/min. hexane/EtOH/MeOH50:25:25). ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.49 (s, 1H), 7.93 (d, 1H),7.50 (d, 1H), 7.43 (m, 2H), 7.31 (m, 2H), 6.71 (s, 1H), 4.11 (m, 1H),3.97 (s, 3H), 3.93 (s, 3H), 3.43 (s, 3H), 1.33 (d, 3H), 0.51 (d, 3H).

Example 1044-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-cyclohexanecarboxylicacid methylamide

The title compound was prepared in analogy to the procedure describedfor intermediate K but using the product from example 98 andN-methylamine hydrochloride. The reaction was performed at 50° C. Afterextraction, the residue was purified by flash chromatography(CH₂Cl₂/MeOH, 97:3→80:20). The residue was triturated in isopropyl etherto afford the title compound. t_(R): 0.92 min (LC-MS 2); ESI-MS:553.4/555.4 [M+H]⁺ (LC-MS 2), ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.42 (s,1H), 7.62 (m, 2H), 7.49 (m, 2H), 5.90 (s, 1H), 4.02 (m, 1H), 3.93 (s,3H), 3.90 (s, 3H), 1.98 (s, 3H), 1.29 (m, 3H), 1.07-2.47 (m, 10H), 0.40(m, 3H).

Example 1055-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 105.1 and intermediate Q.t_(R): 1.06 min (LC-MS 2); ESI-MS: 541.2/543.3 [M+H]⁺ (LC-MS 2).

Step 105.15-Methoxy-1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 105.2. The reaction wasperformed at 110° C. After the reaction was completed, the reactionmixture was suspended in toluene, filtered. The resulting solid wasdried to afford the title compound.

Step 105.2 4-Bromo-5-methoxy-1-methyl-1H-pyridin-2-one

A solution of 4-bromo-2-chloro-5-methoxypyridine (1 g, 4.5 mmol) indimethyl sulfate (1.9 mL, 19.5 mmol) was stirred at 120° C. for 16 h ina sealed tube. After cooling, acetonitrile and a saturated aqueousNaHCO₃ solution were added and the mixture was stirred at rt overweek-end. DCM was added and extracted. The organic layer was dried(Na₂SO₄), filtered and concentrated to give the title compound. t_(R):0.57 min (LC-MS 2); ESI-MS: 218.0/220.0 [M+H]⁺ (LC-MS 2).

Example 106{4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 93.4 and intermediate F.The residue was purified by flash chromatography (CH₂Cl₂/MeOH,99.5:0.5→95:5). t_(R): 1.17-1.20 min (LC-MS 2); ESI-MS: 560.2/562.2[M+H]⁺ (LC-MS 2).

Example 107{4-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl-1-isopropyl)-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 93.4 and intermediate E.The residue was purified by flash chromatography (CH₂Cl₂/MeOH,99.5:0.5→95:5). t_(R): 1.15 min (LC-MS 2); ESI-MS: 546.2/548.1 [M+H]⁺(LC-MS 2).

Example 108{4-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the products from steps 93.4 and 101.1. Theresidue was purified by flash chromatography (CH₂Cl₂/MeOH,99.5:0.5→90:10). t_(R): 0.97 min (LC-MS 2); ESI-MS: 563.2/565.1 [M+H]⁺(LC-MS 2).

Example 1095-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 105.1 and intermediate G.t_(R): 1.04 min (LC-MS 2); ESI-MS: 541.3/543.2 [M+H]⁺ (LC-MS 2).

Example 1105-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 105.1 and intermediate E.After the first purification on preparative HPLC, the product waspurified by SFC chromatography (Column DEAP, 250×30 mm, 5 μm, flow 100mL/min, grad 15-20% over 6 min) to give the title compound. t_(R): 1.07min (LC-MS 2); ESI-MS: 537.3/539.3 [M+H]⁺ (LC-MS 2).

Example 1115-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 97.1 but using the product from step 111.1. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→0:100). t_(R):1.17 min (LC-MS 2); ESI-MS: 568.2/570.2 [M+H]⁺ (LC-MS 2); R_(f)=0.33(heptane/EtOAc, 1:4); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.45-8.42 (m, 1H),7.75 (m, 1H), 7.42-7.13 (m, 6H), 6.63-6.50 (m, 1H), 4.16 (m, 1H),3.98-3.93 (m, 6H), 3.54-3.50 (m, 2H), 3.20 (s, 3H), 1.98-1.90 (m, 3H),0.56 (m, 3H).

Step 111.12-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 111.2 (122 mg, 0.2 mmol) in DME(2.4 mL) was added silver oxide (141 mg, 0.6 mmol) and methyl iodide(305 μl, 4.9 mmol) and the mixture was stirred at 40° C. for 40 h. MeOHwas added and the reaction mixture was concentrated. The product waspurified by flash chromatography (heptane/EtOAc, 100:0→0:100). t_(R):1.20 min (LC-MS 2); ESI-MS: 508.0/510.0/512.0 [M+H]⁺ (LC-MS 2);R_(f)=0.33 (CH₂Cl₂/MeOH, 20:1).

Step 111.22-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-((R)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 111.3 (417 mg, 0.6 mmol) in THF(6 mL) at 0° C. was added TBAF (1.2 mL, 1.2 mmol) and the mixture wasstirred at 0° C. for 15 min. The reaction mixture was diluted in EtOAcand extracted with a 1M NaHCO₃ solution. The organic layer was washedwith brine, dried (Na₂SO₄), filtered and concentrated. The product waspurified by flash chromatography (heptane/EtOAc, 40:60→0:100). t_(R):1.05 min (LC-MS 2); ESI-MS: 494.0/496.1/498.1 [M+H]⁺ (LC-MS 2).

Step 111.32-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 111.4. The product waspurified by flash chromatography (heptane/EtOAc, 100:0→1:1). The residuewas then triturated in diisopropylether, filtered and concentrated.t_(R): 1.63 min (LC-MS 2); ESI-MS: 650.3/652.3/654.3 [M+H]⁺ (LC-MS 2).

Step 111.42-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 111.5. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 20:1). t_(R): 1.67 min(LC-MS 2); ESI-MS: 668.4/670.4/672.4 [M+H]⁺ (LC-MS 2).

Step 111.52-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.3 but using the product from step 111.6 and5-chloro-2-methylaniline. t_(R): 1.80 min (LC-MS 2); ESI-MS:696.4/698.4/700.4 [M+H]⁺ (LC-MS 2); R_(f)=0.33 (heptane/EtOAc, 4:1).

Step 111.62-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate B but using the product from step 111.7. The reactionwas quenched with a 1M aqueous NH₄Cl solution and extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by flash chromatography (heptane/EtOAc,100:0→60:40). t_(R): 1.63 min (LC-MS 2); ESI-MS: 573.3/575.3 [M+H]⁺(LC-MS 2); R_(f)=0.18 (heptane/EtOAc, 3:1).

Step 111.72-Bromo-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

To a solution of the product from step 111.8 (1.5 g, 5.5 mmol) in CH₂Cl₂was added TIPS-Cl (1.8 mL, 8.3 mmol) and imidazole (622 mg, 9.1 mmol)and the reaction mixture was stirred at rt for 2 h. The mixture waspoured into a 1M citric acid solution and extraction with CH₂Cl₂. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The product was purified by flash chromatography(heptane/EtOAc, 4:1). t_(R): 1.50 min (LC-MS 2); ESI-MS: 433.4/435.3[M+H]⁺ (LC-MS 2); R_(f)=0.17 (heptane/MeOH, 3:1).

Step 111.82-Bromo-1-((R)-2-hydroxy-1-methyl-ethyl)-1H-imidazole-4-carboxylic acidethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate A but using the product from step 111.9. The reactionwas performed at rt for 70 h. The product was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5). t_(R): 0.61 min (LC-MS 2); ESI-MS:277.0/279.1 [M+H]⁺ (LC-MS 2); R_(f)=0.27 (CH₂Cl₂/MeOH, 95:5).

Step 111.9 1-((R)-2-Hydroxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

A solution of the product from step A2 (18.1 g, 100 mmol) and D-alaninol(17.3 g, 230 mmol) was stirred at 70° C. for 6 h in a sealed tube. Thereaction mixture was concentrated and purified by flash chromatography(CH₂Cl₂/MeOH, 95:5). t_(R): 0.49 min (LC-MS 2); ESI-MS: 199.1 [M+H]⁺(LC-MS 2); R_(f)=0.11 (CH₂Cl₂/MeOH, 95:5).

Example 1125-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-5-methoxy-pyrimidin-4-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 112.1 (50 mg, 0.05 mmol) in NMP(0.6 mL) was added N-methyl ethanolamine (0.5 mL, 0.05 mmol) and themixture was stirred at 90° C. for 4 h in a sealed tube. The reactionmixture as dissolved in toluene and H₂O and the phases were separated.The organic layer was dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by SFC chromatography (Column Diol, 250×30 mm, 5μm, flow 100 mL/min, grad 18-23% over 6 min) to give the title compound.t_(R): 1.14 min (LC-MS 2); ESI-MS: 585.3/587.3 [M+H]⁺ (LC-MS 2).

Step 112.15-(3-Chloro-4-fluoro-phenyl)-2-(2-chloro-5-methoxy-pyrimidin-4-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 96.1 but using intermediate Q. The reaction was performed at85° C. for 1 h. The product was purified by flash chromatography(CH₂Cl₂/MeOH, 100:0→90:10). t_(R): 1.24 min (LC-MS 2); ESI-MS:546.4/548.4 [M+H]⁺ (LC-MS 2).

Example 1135-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-((R)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 111.2 but using the product from step 113.1. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 99:1→80:20). t_(R): 1.13min (LC-MS 2); ESI-MS: 567.1/569.2 [M+H]⁺ (LC-MS 2); R_(f)=0.12(CH₂Cl₂/MeOH, 20:1).

Step 113.15-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 111.3 and intermediate W.The product was purified by flash chromatography (heptane/EtOAc,100:0→0:100). t_(R): 1.65 min (LC-MS 2); ESI-MS: 725.3 [M+H]⁺ (LC-MS 2);R_(f)=0.12 (heptane/EtOAc, 1:2).

Example 1145-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-[2-[(2-hydroxy-ethyl)-methyl-amino]-5-methoxy-pyrimidin-4-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 112 but using the product from step 96.1. The product waspurified by SFC chromatography (Column Diol, 250×30 mm, 5 μm, flow 100mL/min, grad 17-22% over 6 min) to give the title compound. t_(R): 1.12min (LC-MS 2); ESI-MS: 585.3/587.3 [M+H]⁺ (LC-MS 2).

Example 1155-(5-Chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-(4-methyl-cyclohexyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 115.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The residue was purified bypreparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min.Gradient 5-100% B in 20 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.31min (LC-MS 2); ESI-MS: 524.4/526.4 [M+H]⁺ (LC-MS 2).

Step 115.12-Bromo-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-6-(4-methyl-cyclohexyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 115.2. The reactionmixture was poured into a saturated aqueous NaHCO₃ solution andextracted with EtOAc. The organic layers were washed with a saturatedaqueous NaHCO₃ solution and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was lyophilized to give the title compound asa white solid. t_(R): 1.35 min (LC-MS 2); ESI-MS: 464.3/466.2 [M+H]⁺(LC-MS 2).

Step 115.22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-methyl-cyclohexyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 115.3. The product waspurified by flash chromatography (heptane/EtOAc, 100:0→70:30) to givethe title compound. t_(R): 1.34 min (LC-MS 2); ESI-MS: 482.2/484.2[M+H]⁺ (LC-MS 2).

Step 115.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-methyl-cyclohexyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.3 but using the product from step 115.4 and5-chloro-2-methylaniline. The product was purified by flashchromatography (heptane/EtOAc, 100:0→70:30) to give the title compound.t_(R): 1.55 min (LC-MS 2); ESI-MS: 510.3/512.3 [M+H]⁺ (LC-MS 2).

Step 115.42-Bromo-5-[hydroxy-(4-methyl-cyclohexyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate B but using the product from step 115.5. The productwas purified by flash chromatography (heptane/EtOAc, 100:0→70:30) togive the title compound. t_(R): 1.22 min (LC-MS 2); ESI-MS: 387.2/389.2[M+H]⁺ (LC-MS 2).

Step 115.5 4-Methyl-cyclohexanecarbaldehyde

A mixture of the compound prepared in step 115.6 (8.8 g, 54.7 mmol) andPd/C 10% (5.8 g, 54.7 mmol) in THF (150 mL) and 2,6-lutidine (11.7 g,109 mmol) was stirred for 15.5 h at rt, under a hydrogen atmosphere. Thereaction mixture was filtered through a pad of celite. The crude wasdissolved in CH₂Cl₂ and extracted with 1N HCl then with a saturatedaqueous NaHCO₃ solution. The organic layer was dried (Na₂SO₄), filteredand concentrated.

Step 115.6 4-Methyl-cyclohexanecarbonyl chloride

To a solution of trans-4-methyl-1-cyclohexane carboxylic acid (8.2 g,56.5 mmol) in CH₂Cl₂ (350 mL) at 0° C. was added DMF (44 μl, 0.6 mmol)and oxalyl chloride (11.5 g, 90.0 mmol) dropwise. The reaction mixturewas stirred at rt for 18 h. The reaction mixture was concentrated. Theproduct was used without further purification.

Example 1164-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazole-4-carboxylicacid ethyl ester

To a solution of the product from example 76 (100 mg, 0.2 mmol) in THF(3 mL) at −78° C. was added NaHMDS (181 μL, 0.2 mmol) and the mixturewas stirred at −78° C. for 15 min. Ethyl carbonochloridate (86 μL, 0.9mmol) was added at −78° C. and the mixture was allowed to warm up to rtand stirred for 1 h. The reaction mixture was quenched with a saturatedaqueous NH₄Cl solution, then was diluted in EtOAc and extracted withbrine. The organic layer was dried (Na₂SO₄), filtered and concentrated.The residue was purified by preparative HPLC (Column: Sunfire C18,30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1%TFA in water, B=CH₃CN). t_(R): 1.39 min (LC-MS 2); ESI-MS: 624.4/626.4[M+H]⁺ (LC-MS 2).

Example 1175-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 111.2 but using the product from step 117.1. The product waspurified by flash chromatography (heptane//MeOH, 80:19:1→8:88:4). t_(R):1.06 min (LC-MS 2); ESI-MS: 554.3/556.3 [M+H]⁺ (LC-MS 2); R_(f)=0.05(CH₂Cl₂/MeOH, 20:1).

Step 117.15-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-1-methyl-2-triisopropylsilanyloxy-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 111.3 and2,4-dimethoxypyrimidin-5-ylboronic acid. The product was purified byflash chromatography (heptane/EtOAc, 70:30→0:100). t_(R): 1.58 min(LC-MS 2); ESI-MS: 710.5/712.5 [M+H]⁺ (LC-MS 2); R_(f)=0.33(heptane/EtOAc, 1:4).

Example 1184-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 94.2 and intermediate U.The residue was purified by preparative HPLC (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile20-40% in 16 min) to give the title compound. t_(R): 1.01 min (LC-MS 2);ESI-MS: 514.3/516.3 [M+H]⁺ (LC-MS 2).

Example 1194-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 94.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. The residue was purified bypreparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 40-60% in 16 min) to givethe title compound. t_(R): 1.12 min (LC-MS 3); ESI-MS: 529.2/531.3[M+H]⁺ (LC-MS 3).

Example 1204-Chloro-2-[6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 120.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The residue was purified by SFCchromatography (Column Diol, 250×30 mm, 5 μm, flow 100 mL/min, grad15-20% over 6 min) to give the title compound. t_(R): 1.15 min (LC-MS2); ESI-MS: 549.2/551.2 [M+H]⁺ (LC-MS 2).

Step 120.12-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-4-chloro-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 120.2. The product wastriturated in Et₂O and the resulting suspension was filtered to give thetitle compound as a yellow solid. t_(R): 1.17 min (LC-MS 2); ESI-MS:489.1/491.2 [M+H]⁺ (LC-MS 2).

Step 120.22-Bromo-5-[(5-chloro-2-cyano-phenylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 120.3. t_(R): 1.17 min(LC-MS 2); ESI-MS: 507.2/509.1/511.1 [M+H]⁺ (LC-MS 2).

Step 120.32-Bromo-5-[(5-chloro-2-cyano-phenylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 2-amino-4-chlorobenzonitrile.The reaction mixture was stirred at rt for 20 h.

The mixture was extracted with HCl 1M and with a saturated aqueousNaHCO₃ solution. The organic layers were dried (Na₂SO₄), filtered andconcentrated. The product was triturated in Et₂O, the suspension wasfiltered and the solid was dried in HV. t_(R): 1.36 min (LC-MS 2);ESI-MS: 535.2/537.2/539.1 [M+H]⁺ (LC-MS 2).

Example 1215-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-{2-[(2-hydroxy-ethyl)-methyl-amino]-5-methoxy-pyrimidin-4-yl}-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 112 but using the product from step 121.1. The product waspurified by SFC chromatography (Column 2-EP & 4-EP, 250×30 mm, 5 μm,flow 100 mL/min, grad 17-22% over 6 min) to give the title compound.t_(R): 1.15 min (LC-MS 2); ESI-MS: 581.3/583.3 [M+H]⁺ (LC-MS 2).

Step 121.12-(2-Chloro-5-methoxy-pyrimidin-4-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 96.1 but using intermediate E. t_(R): 1.25 min (LC-MS 2);ESI-MS: 542.2/544.2/546.3 [M+H]⁺ (LC-MS 2).

Example 1225-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 97 but using the product from step 122.1. The mixture wasextracted with CH₂Cl₂. The organic layer was washed with H₂O and brine,dried (Na₂SO₄), filtered and concentrated. The residue was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5). The residue was triturated inEt₂O to give the title compound. t_(R): 0.94 min (LC-MS 2); ESI-MS:541.3/543.3 [M+H]⁺ (LC-MS 2).

Step 122.15-[5-Chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 122.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction was performed at110° C. for 30 min. The product was purified by flash chromatography(CH₂Cl₂/EtOAc, 1:1 and washed with CH₂Cl₂/MeOH, 95:5) The residue waspurified by SFC chromatography (Column 2-ethyl pyridine, 250×30 mm, 5μm, flow 100 mL/min, grad 13-18%) to give the title compound. t_(R):1.16 min (LC-MS 2); ESI-MS: 661.4/663.3 [M+H]⁺ (LC-MS 2).

Step 122.22-Bromo-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 122.3. The residue wastriturated in Et₂O to afford the title compound. t_(R): 1.20 min (LC-MS2); ESI-MS: 601.2/603.3/605.3 [M+H]⁺ (LC-MS 2).

Step 122.32-Bromo-5-[[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino]-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 122.4. The residue wastriturated in Et₂O to afford the title compound. t_(R): 1.20 min (LC-MS2); ESI-MS: 619.3/621.3/623.3 [M+H]⁺ (LC-MS 2).

Step 122.42-Bromo-5-[[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino]-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 122.5. After workup, theresidue was triturated in EtOAc to afford the title compound. t_(R):1.39 min (LC-MS 2); ESI-MS: 647.2/649.3/651.2 [M+H]⁺ (LC-MS 2).

Step 122.5 3-Amino-5-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure describedfor step 100.4 but using the product from step 122.6. The residue waspurified by flash chromatography (hexane/EtOAc, 1:1) to afford the titlecompound. t_(R): 0.86 min (LC-MS 2); ESI-MS: 265.2 [M+H]⁺ (LC-MS 2).

Step 122.6 5-Chloro-1-(4-methoxy-benzyl)-3-nitro-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure describedfor step 100.5 but using 4-methoxybenzyl chloride. The residue wastriturated in Et₂O to give the title compound. t_(R): 0.92 min (LC-MS2); ESI-MS: 295.2 [M+H]⁺ (LC-MS 2).

Example 1234-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylicacid methylamide

To a solution of the product from step 123.1 in CH₂Cl₂ (1.2 mL) in amicrowave vial was added Et₃N (88 μL, 0.6 mmol) and methyl isocyanate(18 mg, 0.3 mmol) and the mixture was stirred at rt for 1.5 h.4-nitrophenyl chloroformate (59 mg, 0.3 mmol) was added and the mixturewas stirred at rt for 30 min. Methylamine 2M in THF (837 μL, 1.7 mmol)was added and the mixture was stirred at rt for 18 h and at 50° C. for1.5 h. The reaction mixture was diluted with EtOAc and extracted with asaturated aqueous NaHCO₃ solution. The organic layer was dried (MgSO₄),filtered and concentrated. The product was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min). The residue was purified byflash chromatography (CH₂Cl₂/MeOH, 100:0→90:10) to give the titlecompound as a white solid. t_(R): 0.90 min (LC-MS 2); ESI-MS:554.6/556.3 [M+H]⁺ (LC-MS 2).

Step 123.16-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-piperidin-4-yl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 123.2 (500 mg, 0.8 mmol) wasadded a 4M HCl solution in dioxane (2 mL) and the mixture was stirred atrt for 4.5 h. At 0° C., the pH was adjusted to 7-8 with a saturatedaqueous NaHCO₃ solution. The aqueous layer was saturated with NaCl andwas extracted with THF/AcOEt 1:3. The organic layer was dried (MgSO₄),filtered and concentrated to afford the title compound. t_(R): 0.76 min(LC-MS 2); ESI-MS: 497.3/499.4 [M+H]⁺ (LC-MS 2).

Step 123.24-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 123.3. The residue waspurified by flash chromatography (CH₂Cl₂/EtOAc, 80:20→0:100). A secondflash chromatography was performed (CH₂Cl₂/MeOH, 100:0→90:10). Theresidue was purified by preparative chromatography (C18) to affort thetitle compound. t_(R): 1.18 min (LC-MS 2); ESI-MS: 597.4/599.3 [M+H]⁺(LC-MS 2).

Step 123.34-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product was step 123.4. The crude waspurified by flash chromatography (CH₂Cl₂/EtOAc, 80:20→0:100). t_(R):1.20 min (LC-MS 2); ESI-MS: 537.3/539.3 [M+H]⁺ (LC-MS 2).

Step 123.44-{[(2-Bromo-5-carboxy-3-isopropyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 123.5. t_(R): 0.94 min(LC-MS 2); ESI-MS: 555.3/557.4 [M+H]⁺ (LC-MS 2).

Step 123.54-{[(2-Bromo-5-ethoxycarbonyl-3-isopropyl-3H-imidazol-4-yl)-(4-chloro-phenyl)-methyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.3 but using intermediate B andN-(4-aminocyclohexyl)pivalamide. The product was purified by flashchromatography (heptane/EtOAc, 80:20→0:100). t_(R): 1.41 min (LC-MS 2);ESI-MS: 583.3/585.3 [M+H]⁺ (LC-MS 2).

Example 1244-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 100.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The product was purified byflash chromatography (CH₂Cl₂/MeOH, 95:5). The resulting foam waspurified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 20-60% in 20 min). Theresulting solid was purified by SFC chromatography (Column Hilic silica,100 mm, gradient 25-30%). The residue was triturated in Et₂O to affordthe title compound. t_(R): 0.86 min (LC-MS 2); ESI-MS: 546.3/548.3[M+H]⁺ (LC-MS 2).

Example 1254-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-piperidine-1-carboxylicacid methyl ester

To a solution of the product from step 123.1 (118 mg, 0.2 mmol) inCH₂Cl₂ was added Et3N (168 μL, 12 mmol), and methyl carbonochloridate(37 μL, 0.5 mmol) and the mixture was stirred at rt for 15 min. Themixture was quenched with H₂O and the layers were separated. The aqueouslayer was washed with CH₂Cl₂. The organic layer was dried (MgSO₄),filtered and concentrated. The residue was purified by preparative HPLC(C18). t_(R): 1.02 min (LC-MS 2); ESI-MS: 555.3/557.4 [M+H]⁺ (LC-MS 2).

Example 1262-[4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl]-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 126.1 and intermediate G.The reaction mixture was diluted with brine, and was extracted withEtOAc. The organic layer was washed with brine, dried (MgSO₄), filtered,and concentrated. The residue was purified by flash chromatography(CH₂Cl₂/MeOH/NH₃aq., 200:10:1). t_(R): 1.02 min (LC-MS 2); ESI-MS:582.4/584.3 [M+H]⁺ (LC-MS 2).

Step 126.12-[5-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor intermediate F but using the product from step 126.2. The reactionwas performed at 90° C. The product was used without furtherpurification.

Step 126.2 2-(4-Chloro-5-methoxy-pyridin-2-yl)-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor intermediate F but using the product from step 126.3 andmethanamine. The reaction was performed at rt. The reaction mixture wasdiluted with EtOAc and extracted with a saturated aqueous NaHCO₃solution. The organic layer was washed with a saturated aqueous NaHCO₃solution, dried (MgSO₄), filtered and concentrated. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 100:0→90:10). The residuewas triturated in Et₂O and CH₂Cl₂ to afford the title compound. t_(R):0.58 min (LC-MS 2); ESI-MS: 215.1 [M+H]⁺ (LC-MS 2).

Step 126.3 (4-Chloro-5-methoxy-pyridin-2-yl)-acetic acid

To a suspension of 2-(4-chloro-5-methoxypyridin-2-yl)acetonitrile (150mg, 0.8 mmol) in EtOH (2 mL) was added a solution of KOH (184 mg, 3.3mmol) in H₂O (2 mL) and the mixture was stirred at 80° C. for 1.5 h. at0° C., th pH was adjusted to 3-4 with HCl 1M. Sodium chloride, THF andEtOAc were added and the phases were separated. The organic layer wasdried (MgSO₄), filtered and concentrated to afford the title compound.t_(R): 0.59 min (LC-MS 2); ESI-MS: 202.1 [M+H]⁺ (LC-MS 2).

Example 1275-(5-Chloro-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 97 but using the product from step 127.1. The mixture wasextracted with CH₂Cl₂ and a saturated aqueous NaHCO₃ solution. Theorganic layer was washed with H₂O and brine, dried (Na₂SO₄), filteredand concentrated. The residue was triturated in CH₂Cl₂ to give the titlecompound. t_(R): 0.98 min (LC-MS 2); ESI-MS: 554.3/556.4 [M+H]⁺ (LC-MS2).

Step 127.15-[5-Chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 127.2 and intermediate W.The reaction was performed at 110° C. The product was purified bypreparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min.Gradient 30-70% B in 20 min; A=0.1% TFA in water, B=CH₃CN) to afford thetitle compound. t_(R): 1.17 min (LC-MS 2); ESI-MS: 674.4/676.4 [M+H]⁺(LC-MS 2).

Step 127.22-Bromo-5-[5-chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 127.3. Afterextraction, the residue was triturated in EtOAc to afford the titlecompound. t_(R): 1.10 min (LC-MS 2); ESI-MS: 601.3/603.3/605.2 [M+H]⁺(LC-MS 2).

Step 127.32-Bromo-5-[[5-chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 127.4. After extraction, theresidue was triturated in Et₂O to afford the title compound. t_(R): 1.06min (LC-MS 2); ESI-MS: 619.3/621.3/623.2 [M+H]⁺ (LC-MS 2).

Step 127.42-Bromo-5-[[5-chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and the product from step 127.5.The reaction mixture was stirred at rt for 16 h. The residue waspurified by flash chromatography (CH₂Cl₂/EtOAc, 1:1). The product wasthen triturated in Et₂O to afford the title compound. t_(R): 1.23 min(LC-MS 2); ESI-MS: 647.3/649.4/651.3 [M+H]⁺ (LC-MS 2).

Step 127.5 5-Amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one

A saturated aqueous solution of NH₄Cl (99 mL) was added to a solution ofthe intermediate prepared in step 127.6 (6.8 g, 23.0 mmol) in EtOH (300mL). After a 15 min stirring, iron powder (6.4 g, 115 mmol) was addedand the resulting mixture was heated to reflux, stirred for 1 h,concentrated, diluted with EtOH, and filtered through a pad of celite.The filtrate was concentrated. The residue was purified by flashchromatography (CH₂Cl₂/MeOH, 100:0→96.5:3.5). t_(R): 0.61 min (LC-MS 2);ESI-MS: 265.2 [M+H]⁺ (LC-MS 2); R_(f)=0.53 (CH₂Cl₂/MeOH, 9:1).

Step 127.6 3-Chloro-1-(4-methoxy-benzyl)-5-nitro-1H-pyridin-2-one

4-methoxybenzyl bromide (5.0 mL, 34.4 mmol) was added to a cold (0° C.)mixture 3-chloro-2-hydroxy-5-nitropyridine (5 g, 28.6 mmol) and K₂CO₃(7.9 g, 57.3 mmol) in DMF (25 mL). The reaction mixture was allowed towarm to rt, stirred for 2 h, quenched by addition of a saturated aqueousNaHCO₃ solution, and extracted with EtOAc. The organic layer was washedwith brine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by trituration in EtOAc. t_(R): 0.98 min (LC-MS 2); ESI-MS:295.2 [M+H]⁺ (LC-MS 2).

Example 1282-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 128.1 and intermediate U.After extraction, the residue was purified by preparative HPLC to givethe title compound. t_(R): 0.80 min (LC-MS 2); ESI-MS: 525.4/527.3[M+H]⁺ (LC-MS 2).

Step 128.12-Bromo-6-(4-chloro-phenyl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 128.2. The reactionmixture was diluted with toluene and extracted with H₂O and washed withbrine. The organic layer was dried (Na₂SO₄), filtered and concentrated.The residue was triturated in diisopropylether/EtOAc 10:1 to give thetitle compound. t_(R): 0.91 min (LC-MS 2); ESI-MS: 480.1/482.2 [M+H]⁺(LC-MS 2).

Step 128.22-Bromo-5-[(4-chloro-phenyl)-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-ylamino)-methyl]-1-isopropyl-1H-imidazol-4-carboxyliacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 128.3. t_(R): 0.79 min(LC-MS 2); ESI-MS: 498.2/500.3/502.4 [M+H]⁺ (LC-MS 2).

Step 128.32-Bromo-5-[(4-chloro-phenyl)-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and the product from step 128.4.The reaction mixture was extracted with a saturated aqueous NaHCO₃solution. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The product was purified by flash chromatography(heptane/EtOAc/Et₃N, 100:0:1→0:100:1) to provide the title compound.t_(R): 1.11 min (LC-MS 2); ESI-MS: 526.3/528.3/530.4 [M+H]⁺ (LC-MS 2).

Step 128.4 5-Amino-1,3-dimethyl-tetrahydro-pyrimidin-2-one

A mixture of the compound prepared in step 128.5 (2.5 g, 11.1 mmol) andPd/C 10% (500 mg) in EtOH (70 mL) was stirred for 13.5 h at rt, under ahydrogen atmosphere. The reaction mixture was filtered through a pad ofcelite, washed with THF and MeOH and concentrated. The residue wasdissolved in EtOAc and extracted with cold HCl 1N. The aqueous phase wasbasified with a saturated aqueous NaHCO₃ solution. The resulting aqueousphase was extracted with CH₂Cl₂/isopropanol 3:1. The organic layers weredried (Na₂SO₄), filtered and concentrated. ESI-MS: 144.1 [M+H]⁺ (MS 1).

Step 128.5 5-Azido-1,3-dimethyl-tetrahydro-pyrimidin-2-one

To a solution of the product from step 128.6 (3.2 g, 14.3 mmol) in DMF(75 mL) at rt was added sodium azide (1.9 g, 28.7 mmol) and the mixturewas stirred at 70° C. for 13 h. The mixture was diluted withCH₂Cl₂/isopropanol 3:1 and extracted with a saturated aqueous NaHCO₃solution. The organic phase was dried (Na₂SO₄), filtered andconcentrated. ESI-MS: 170.1 [M+H]⁺ (MS 1).

Step 128.6 Methanesulfonic acid1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 128.7. The reaction mixturewas diluted with H₂O and a saturated aqueous NaHCO₃ solution andextracted with CH₂Cl₂/isopropanol 3:1. The organic layers were dried(Na₂SO₄), filtered and concentrated. ESI-MS: 223.1 [M+H]⁺ (MS 1).

Step 128.7 5-Hydroxy-1,3-dimethyl-tetrahydro-pyrimidin-2-one

To a solution of the product from step 128.8 (9.1 g, 28 mmol) in EtOH(70 mL) was added a 1M HCl (140 mL, 140 mmol) and the mixture wasstirred at rt for 3 h at 70° C. The mixture was concentrated, and the pHof the resulting aqueous phase was adjusted to 5 with a saturatedaqueous NaHCO₃ solution. The aqueous layer was saturated with NaCl andwas extracted with CH₂Cl₂/isopropanol 3:1. The organic layer was dried(Na₂SO₄), filtered and concentrated to afford the title compound. t_(R):0.33 min (LC-MS 2); ESI-MS: 145.1 [M+H]⁺ (LC-MS 2).

Step 128.81,3-Dimethyl-5-triisopropylsilanyloxy-tetrahydro-pyrimidin-2-one

The title compound was prepared in analogy to the procedure describedfor step 100.5 but using the product from step 128.9. The reactionmixture quenched by addition of water, and extracted with toluene. Theaqueous layer was washed with EtOAc. The combined organic layers werewashed with a saturated aqueous NaHCO₃ solution, dried (Na₂SO₄),filtered, and concentrated. The residue was used without furtherpurification. t_(R): 1.33 min (LC-MS 2); ESI-MS: 301.3 [M+H]⁺ (LC-MS 2).

Step 128.9 5-Triisopropylsilanyloxy-tetrahydro-pyrimidin-2-one

To a solution of the product prepared in step 128.10 (27.8 g, 113 mmol)in MeOH (450 mL) was added S,S-dimethyl carbonodithioate (17.7 mL, 169mmol) and the mixture was stirred at 60° C. for 20 h. The reactionmixture was concentrated. The residue was purified by flashchromatography (CH₂Cl₂/MeOH, 100:0→5:1) to afford the title compound.ESI-MS: 273.3 [M+H]⁺ (LC-MS 2-flow injection).

Step 128.10 2-Triisopropylsilanyloxy-propane-1,3-diamine

To a solution of 1,3-diaminopropan-2-ol (19.4 g, 215 mmol) in CH₂Cl₂(250 mL) at 0° C. was added TIPS-Cl (50.2 mL, 237 mmol) and Et₃N (90 mL,646 mmol) and the reaction mixture was stirred at rt for 20 h. Themixture was diluted with CH₂Cl₂. The organic layer was washed with asaturated aqueous NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The product was used without further purification. ESI-MS:247.3 [M+H]⁺ (LC-MS 2-flow injection).

Example 1296-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 128.1 and intermediate W.After extraction, the residue was purified by preparative HPLC. Theresidue was triturated in diisopropylether to give the title compound.t_(R): 1.00 min (LC-MS 2); ESI-MS: 553.4/555.4 [M+H]⁺ (LC-MS 2).

Example 1304-[5-(3-Chloro-2-fluoro-phenyl)-2-(5-cyanomethyl-2-methoxy-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 130.1 and intermediateAB. The reaction was performed at 80° C. After extraction, the residuewas purified by flash chromatography (CH₂Cl₂/EtOAc, 80:20→0:100) toafford the title compound. t_(R): 1.07 min (LC-MS 2); ESI-MS:540.4/542.2 [M+H]⁺ (LC-MS 2).

Step 130.1[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate S but using (3-bromo-4-methoxy-phenyl)-acetonitrile.The reaction mixture was diluted with EtOAc and extracted with brine,then washed with H₂O. The organic layer was dried (MgSO₄), filtered andconcentrated. The residue was purified by flash chromatography(CH₂Cl₂/EtOAc, 95:5→0:100) to afford the title compound. t_(R): 1.03 min(LC-MS 2).

Example 1314-[5-(5-Chloro-2-methyl-phenyl)-2-(5-cyanomethyl-2-methoxy-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H and the product from step 131.1.The reaction mixture was dissolved in EtOAc and extracted with asaturated aqueous NaHCO₃ solution. The organic layer was washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→0:100). t_(R):1.04 min (LC-MS 2); ESI-MS: 537.4/539.4 [M+H]⁺ (LC-MS 2).

Step 131.1[6-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetonitrile

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 131.2. The reactionmixture was diluted with EtOAc and extracted with brine, then washedwith H₂O. The organic layer was dried (MgSO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 70:30→0:100) to afford the title compound. t_(R): 0.98min (LC-MS 2); ESI-MS: 275.1 [M+H]⁺ (LC-MS 2).

Step 131.2 (5-Bromo-6-methoxy-pyridin-3-yl)-acetonitrile

To a suspension of the product from step 131.3 (3.9 g, 14.0 mmol) in H₂Owas added NaCN (750 mg, 15.3 mmol) and the mixture was stirred at 50° C.for 1.5 h. CH₂Cl₂ and a saturated aqueous NaHCO₃ solution were added andthe phases were separated. The organic layer was washed with H₂O andbrine, dried (MgSO₄), filtered and concentrated. The crude product waspurified by flash chromatography (heptane/EtOAc, 80:20→0:100). t_(R):0.88 min (LC-MS 2).

Step 131.3 3-Bromo-5-bromomethyl-2-methoxy-pyridine

To a solution of the product from step 131.4 (3.0 g, 14.7 mmol), wasadded NBS (3.1 g, 17.6 mmol) and AIBN (121 mg, 0.7 mmol) and the mixturewas stirred at 80° C. for 1 h. H₂O and CH₂Cl₂ were added and the phaseswere separated. The organic layer was dried (MgSO₄), filtered andconcentrated. The crude product was purified by flash chromatography(heptane/EtOAc, 95:5→0:100). t_(R): 1.10 min (LC-MS 2).

Step 131.4 3-Bromo-2-methoxy-5-methyl-pyridine

To a solution of 3-bromo-2-chloro-5-methylpyridine (5 g, 24.2 mmol) inMeOH (80 mL) was added a solution of sodium methoxide 5.4M in MeOH (25mL, 135 mmol) and the mixture was stirred at 65° C. for 32 h. Theresulting suspension was filtered and the mother liquor wasconcentrated. Et₂O and H₂O were added and the phases were separated. Theorganic layer was washed with H₂O and brine, dried (MgSO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc: 90:10→0:100) to afford the title compound. t_(R): 1.03min (LC-MS 2).

Example 1324-[5-(3-Chloro-2-fluoro-phenyl)-2-(5-cyanomethyl-2-methoxy-pyridin-3-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB and the product from step131.1. The reaction mixture was dissolved in EtOAc and extracted with asaturated aqueous NaHCO₃ solution. The organic layer was washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→0:100). t_(R):1.03 min (LC-MS 2); ESI-MS: 541.3/543.3 [M+H]⁺ (LC-MS 2).

Example 133{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate G and the product from step 131.1.The reaction mixture was dissolved in EtOAc and extracted with asaturated aqueous NaHCO₃ solution. The organic layer was washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→0:100). t_(R):1.17 min (LC-MS 2); ESI-MS: 550.3/552.3 [M+H]⁺ (LC-MS 2).

Example 1344-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,56-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB and the product from step 93.4.The reaction mixture was poured into brine and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc/MeOH, 10:88:2→0:98:2). t_(R): 0.98 min (LC-MS 2); ESI-MS:541.4/543.4 [M+H]⁺ (LC-MS 2).

Example 1354-[5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H and the product from step 93.4.The reaction mixture was poured into brine and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc/MeOH, 10:88:2→0:98:2). t_(R): 1.00 min (LC-MS 2); ESI-MS:537.4/539.3 [M+H]⁺ (LC-MS 2).

Example 136{4-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate G and the product from step 93.4.The reaction mixture was poured into brine and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc/MeOH, 10:88:2→0:98:2). t_(R): 1.12 min (LC-MS 2); ESI-MS:550.2/552.2 [M+H]⁺ (LC-MS 2).

Example 137{5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H and the product from step 137.1.The reaction was performed at 80° C. The reaction mixture was pouredinto a saturated aqueous NaHCO₃ solution and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 1:4). t_(R): 1.13 min (LC-MS 2); ESI-MS: 584.3/586.4[M+H]⁺ (LC-MS 2).

Step 137.1[6-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-aceticacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 137.2 andPdCl₂(PPh₂)ferrocene.CH₂Cl₂. The reaction was performed at 90° C. Afterextraction, the residue was purified by flash chromatography(heptane/EtOAc, 80:20→0:100) to afford the title compound. t_(R): 1.11min (LC-MS 2); ESI-MS: 322.3 [M+H]⁺ (LC-MS 2).

Step 137.2 (5-Bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester

To a solution of the product from step 137.3 (400 mg, 1.6 mmol) inCH₂Cl₂ (0.8 mL) was added EtOH (285 □L, 4.8 mmo

stirred at rt 15 h. H₂O and EtOAc were added and the phases wereseparated. The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated. The residue was purified by flashchromatography (heptane/EtOAc, 85:15→0:100). t_(R): 1.05 min (LC-MS 2);ESI-MS: 274.1/276.1 [M+H]⁺ (LC-MS 2).

Step 137.3 (5-Bromo-6-methoxy-pyridin-3-yl)-acetic acid

The title compound was prepared in analogy to the procedure describedfor step 126.3 but using the product from step 131.2. After the pH wasadjusted to 3 with 1M HCl, CH₂Cl₂ was added and the phases wereseparated. The organic layer was dried (MgSO₄), filtered andconcentrated to afford the title compound. t_(R): 0.75 min (LC-MS 2);ESI-MS: 243.9/245.9 [M+H]⁺ (LC-MS 2).

Example 138{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid

The title compound was prepared in analogy to the procedure describedfor example 140 but using the product from example 138.1. t_(R): 0.96min (LC-MS 2); ESI-MS: 560.4/562.5 [M+H]⁺ (LC-MS 2).

Step 138.1{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate AB and the product from step137.1. The reaction was performed at 70° C. The reaction mixture waspoured into brine and extracted with EtOAc. The organic layer was washedwith a saturated aqueous NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 80:20→0:100). t_(R): 1.12 min (LC-MS 2); ESI-MS: 588.4[M+H]⁺ (LC-MS 2).

Example 1394-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carboxylicacid amide

The title compound was prepared in analogy to the procedure describedfor step 94.1 but using the product from example 170. The residue waspurified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-90% in 16 min) to givethe title compound. t_(R): 1.04 min (LC-MS 2); ESI-MS: 551.3/553.3[M+H]⁺ (LC-MS 2).

Example 140{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid

To a solution of the product from step 140.1 (119 mg, 0.2 mmol) inTHF/MeOH (0.8 mL, 1:1) was added LiOH (394 μL, 0.8 mmol, 2M) and themixture was stirred at rt for 30 min. The reaction mixture was pouredinto a 1M citric acid solution, H₂O was added and the mixture wasextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated to afford the title compound. t_(R): 1.09 min (LC-MS 2);ESI-MS: 569.3/571.3 [M+H]⁺ (LC-MS 2).

Step 140.1{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticaid ethyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 137.1 and intermediate G.The reaction mixture was diluted with a saturated aqueous NaHCO₃solution, and was extracted with EtOAc. The organic layer was washedwith brine, dried (Na₂SO₄), filtered, and concentrated. The residue waspurified by flash chromatography (hexane/EtOAc, 4:1). t_(R): 1.26 min(LC-MS 2); ESI-MS: 597.3/599.3 [M+H]⁺ (LC-MS 2).

Example 141{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid

A solution of the product from step 141.1 (115 mg, 0.17 mmol) in TFA (1mL) was stirred in a microwave oven at 100° C. for 30 min. The reactionmixture was concentrated, diluted with CH₂Cl₂ and extracted with asaturated aqueous NaHCO₃ solution. The organic layer was washed withbrine, dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (CH₂Cl₂/MeOH, 95:5) then triturated inEt₂O to afford the title compound. t_(R): 0.88 min (LC-MS 2); ESI-MS:541.3/543.3 [M+H]⁺ (LC-MS 2); R_(f)=0.21 (CH₂Cl₂/MeOH, 92.5:7.5).

Step 141.15-[5-Chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 127.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the residuewas purified by flash chromatography (CH₂Cl₂/MeOH, 95:5). The residuewas then purified by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5μm. Flow: 30 mL/min. Gradient 25-70% B in 20 min; A=0.1% TFA in water,B=CH₃CN). t_(R): 1.08 min (LC-MS 2); ESI-MS: 661.5/663.5 [M+H]⁺ (LC-MS2); R_(f)=0.10 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 1424-[(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 53. t_(R): 12.90 min (Column:Chiralpak AD-H, Flow 2.0 mL/min. heptane/EtOH 1:1. Detection: UV 210nm). t_(R): 0.92 min (LC-MS 2); ESI-MS: 518.4/520.3 [M+H]⁺ (LC-MS 2);¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.10 (s, 1H), 4.83 (d, 2H), 7.52-7.44(m, 4H), 7.19 (m, 1H), 7.08 (s, 2H), 6.60 (s, 1H), 4.11 (m, 1H), 3.82(s, 3H), 1.33 (d, 3H), 0.49 (d, 3H).

Example 1434-[(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 53. t_(R): 8.92 min (Column: ChiralpakAD-H, Flow 2.0 mL/min. heptane/EtOH 1:1. Detection: UV 210 nm). t_(R):0.92 min (LC-MS 2); ESI-MS: 518.4/520.3 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.10 (s, 1H), 4.83 (d, 2H), 7.52-7.44 (m, 4H),7.19 (m, 1H), 7.08 (s, 2H), 6.60 (s, 1H), 4.11 (m, 1H), 3.82 (s, 3H),1.33 (d, 3H), 0.49 (d, 3H).

Example 1445-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[3-(2-methyl-3H-imidazol-4-yl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 144.1 and intermediate E.The residue was purified by preparative HPLC (Column: Sunfire C18,30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1%TFA in water, B=CH₃CN). The residue was triturated in diisopropyletherto afford the title compound. t_(R): 1.02 min (LC-MS 2); ESI-MS:556.3/558.3 [M+H]⁺ (LC-MS 2).

Step 144.12-Methyl-5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 144.2. The reactionwas performed at 115° C. The reaction mixture was dissolved in toluene,filtered over celite and the mother liquor was concentrated to give thetitle compound (50% purity). t_(R): 0.76 min (LC-MS 2); ESI-MS: 285.3[M+H]⁺ (LC-MS 2).

Step 144.2 5-(3-Bromo-phenyl)-2-methyl-1H-imidazole

To a solution of the product from step 144.3 (2.3 g, 8.7 mmol) in xylene(45 mL) was added ammonium acetate (3.4 g, 463.6 mmol) and the mixturewas stirred at 140° C. for 3 h. The reaction mixture was cooled to rtand concentrated. The residue was diluted with EtOAc and extracted witha saturated aqueous NaHCO₃ solution. The organic layer was dried(Na²SO₄), filtered and concentrated. The product was purified by flashchromatography (heptanes/EtOAc, 100:0→0:100) to give the title compound.t_(R): 0.61 min (LC-MS 2); ESI-MS: 234.9/237.0 [M+H]⁺ (LC-MS 2).

Step 144.3 N-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-acetamide

To a solution of the product from step 144.4 (4 g, 13.6 mmol), AcOH (854μl, 14.9 mmol) and HATU (6.2 g, 16.3 mmol) in DMF (45 mL) was added DIEA(9.5 mL, 54.2 mmol) and the mixture was stirred at rt for 1 h. Thereaction mixture was concentrated. The residue was diluted with EtOAcand extracted with H₂O and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (heptanes/EtOAc, 30:70→0:100) to give the title compound.t_(R): 0.73 min (LC-MS 2); ESI-MS: 256.0 [M+H]⁺ (LC-MS 2).

Step 144.4 2-Amino-1-(3-bromo-phenyl)-ethanone hydrobromide

To a solution of HBr (18.2 mL, 161 mmol) in MeOH (100 mL) was added theproduct from step 144.5 (22.5 g, 53.7 mmol) and the mixture was stirredat rt over 4 days. The reaction mixture was concentrated and cooled to0° C. The resulting suspension was filtered and the solid was dried toafford the title compound. t_(R): 0.49 min (LC-MS 2); ESI-MS:213.9/216.1 [M+H]⁺ (LC-MS 2).

Step 144.51-[2-(3-Bromo-phenyl)-2-oxo-ethyl]-3,5,7-triaza-1-azonia-tricyclo[3.3.1.1*3,7*]decanehydrobromide

To a solution of hexamethylenetetramine (8.2 g, 58.4 mmol) in CHCl₃ (150mL) was added 2,3′-dibromoacetophenone (15.2 g, 53 mmol) and the mixturewas stirred at rt for 20 h. TNME was added and the resulting solid wasfiltered, dried in HV to afford the title compound. t_(R): 0.55 min(LC-MS 2); ESI-MS: 337.1/339.1 [M+H]⁺ (LC-MS 2).

Example 1456-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 128.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the residuewas purified by preparative HPLC. The residue was lyophilized in dioxaneto give the title compound. t_(R): 0.91 min (LC-MS 2); ESI-MS:540.4/542.3 [M+H]⁺ (LC-MS 2).

Example 146{5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid

The title compound was prepared in analogy to the procedure describedfor example 140 but using the product from example 137. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 100:0→0:100) to give thetitle compound. t_(R): 0.98 min (LC-MS 2); ESI-MS: 556.3/558.3 [M+H]⁺(LC-MS 2).

Example 1472-{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-N-methyl-acetamide

To a suspension of the product from step 140 (105 mg, 0.18 mmol), EDC(44 mg, 0.23 mmol) and HOBT (21 mg, 0.14 mmol) in DMF (1.8 mL) was addedEt₃N (89 μL, 0.64 mmol) and the mixture was stirred at rt 5 min.Methylamine hydrochloride (18 mg, 0.27 mmol) was added and the mixturewas stirred at rt 20 h. The reaction mixture was poured into a 1Maqueous NaHCO₃ solution and extracted with EtOAc. The organic layer waswashed with brine, dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by flash chromatography (CH₂Cl₂/MeOH, 96:4→95:5) togive the title compound. t_(R): 1.07 min (LC-MS 2); ESI-MS: 582.4/584.3[M+H]⁺ (LC-MS 2).

Example 1482-{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor example 147 but using the product from example 138. t_(R): 0.94 min(LC-MS 2); ESI-MS: 573.3/575.3 [M+H]⁺ (LC-MS 2).

Example 1495-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((S)-2-hydroxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 111.2 but using the product from step 149.1. The residue waspurified by flash chromatography (CH₂Cl₂/MeOH, 100:0→95:5). t_(R): 1.06min (LC-MS 2); ESI-MS: 554.3/556.4 [M+H]⁺ (LC-MS 2); R_(f)=0.24(CH₂Cl₂/MeOH, 95:5).

Step 149.15-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 149.2 and2,4-dimethoxypyrimidin-5-ylboronic acid. The residue was purified byflash chromatography (heptane/EtOAc, 60:40→0:100). t_(R): 1.59 min(LC-MS 2); ESI-MS: 710.5/712.5 [M+H]⁺ (LC-MS 2).

Step 149.22-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 149.3. The product waspurified by flash chromatography (heptane/EtOAc, 2:1). The residue wasthen triturated in diisopropylether, filtered and concentrated. t_(R):1.65 min (LC-MS 2); ESI-MS: 650.3/652.3/654.4 [M+H]⁺ (LC-MS 2);R_(f)=0.25 (heptane/EtOAc, 2:1).

Step 149.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 149.4. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 20:1). t_(R): 1.66 min(LC-MS 2); ESI-MS: 668.3/670.4/672.4 [M+H](LC-MS 2).

Step 149.42-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 93.3 but using the product from step 149.5 and5-chloro-2-methylaniline. t_(R): 1.81 min (LC-MS 2); ESI-MS:696.4/698.4/700.4 [M+H]⁺ (LC-MS 2); R_(f)=0.33 (heptane/EtOAc, 4:1).

Step 149.52-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate B but using the product from step 149.6 and4-chlorobenzaldehyde. The reaction was quenched with a 1M aqueous NH₄Clsolution and extracted with EtOAc. The organic layer was dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (heptane/EtOAc, 4:1). t_(R): 1.65 min (LC-MS 2); ESI-MS:573.3/575.3 [M+H]⁺ (LC-MS 2); R_(f)=0.18 (heptane/EtOAc, 3:1).

Step 149.62-Bromo-1-((S)-1-methyl-2-triisopropylsilanyloxy-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 111.7 but using the product from step 149.7. The product waspurified by flash chromatography (heptane/EtOAc, 5:1→3:1). t_(R): 1.49min (LC-MS 2); ESI-MS: 433.3/435.3 [M+H]⁺ (LC-MS 2); R_(f)=0.17(heptane/EtOAc, 3:1).

Step 149.72-Bromo-1-((S)-2-hydroxy-1-methyl-ethyl)-1H-imidazole-4-carboxylic acidethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate A but using the product from step 149.8. The reactionwas performed at rt for 4 days. The product was purified by flashchromatography (heptane/EtOAc/MeOH, 1:5:0→0:98:2). The residue wastriturated in TBME, then purified by flash chromatography(heptane/EtOAc, 1:5). t_(R): 0.61 min (LC-MS 2); ESI-MS: 277.1/279.2[M+H]⁺ (LC-MS 2); R_(f)=0.27 (CH₂Cl₂/MeOH, 95:5).

Step 149.8 1-((S)-2-Hydroxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 111.9 but using L-alaninol. t_(R): 0.48 min (LC-MS 2); ESI-MS:199.1 [M+H]⁺ (LC-MS 2).

Example 150{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid ethyl ester

To a solution of intermediate AB (80 mg, 0.17 mmol) and the product fromstep 137.1 (82 mg, 0.25 mmol) in DME (1.7 mL) was added K₃PO₄ (71 mg,0.33 mmol), Pd(OAc)₂ (3 mg, 0.01 mmol) and S-Phos (10 mg, 0.02 mmol) andthe mixture was stirred at 70° C. for 2 h. The reaction mixture wasallowed to cool down to rt, poured into EtOAc and extracted with brine.The organic layer was dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by flash chromatography (heptane/EtOAc:80:20→0:100) to afford the title compound. t_(R): 1.12 min (LC-MS 2);ESI-MS: 588.4/590.3 [M+H]⁺ (LC-MS 2); R_(f): 0.21 (CH₂Cl₂/EtOAc 1:4).

Example 1512-{5-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor example 147 but using the product from example 146 and methylaminehydrochloride. t_(R): 0.97 min (LC-MS 2); ESI-MS: 569.3/571.3 [M+H]⁺(LC-MS 2); R_(f)=0.15 (CH₂Cl₂/MeOH, 20:1).

Example 152{5-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-6-methoxy-pyridin-3-yl}-aceticacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate G and the product from step 137.1.The reaction was performed at 80° C. The reaction mixture was pouredinto a saturated aqueous NaHCO₃ solution and extracted with EtOAc. Theorganic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 1:4). t_(R): 1.26 min (LC-MS 2); ESI-MS: 597.3/599.3[M+H]⁺ (LC-MS 2).

Example 1536-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-6-methyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from example 76 (100 mg, 0.18 mmol) in THF(2 mL) at −78° C. was added KHMDS (217 μL, 0.22 mmol, 1M in THF) and themixture was stirred at −78° C. for 15 min. Methyl iodide (34 μL, 0.54mmol) was added and the mixture was allowed to warm to rt and themixture was stirred at rt for 20 h. The reaction mixture was dilutedwith EtOAc and extracted with a 5% citric acid solution. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by preparative HPLC, then the residue waslyophilized in dioxane. t_(R): 1.25 min (LC-MS 2); ESI-MS: 566.3/568.2[M+H]⁺ (LC-MS 2).

Example 1542-{3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor intermediate F but using the product from step 154.1 and methylamine(2M in THF). The reaction was performed at rt. The reaction mixture wasdiluted with EtOAc and extracted with H₂O. The organic layer was dried(Na₂SO₄), filtered and concentrated. The residue was purified bypreparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) to givethe title compound. t_(R): 1.13 min (LC-MS 2); ESI-MS: 577.4/579.4[M+H]⁺ (LC-MS 2).

Step 154.1{3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-aceticacid

The title compound was prepared in analogy to the procedure describedfor step 64.1 but using the product from step 154.2. The reaction wasperformed at rt. The reaction mixture was diluted with EtOAc andextracted with 5% citric acid. The organic layer was dried (Na₂SO₄),filtered and concentrated. t_(R): 1.16 min (LC-MS 2); ESI-MS:564.4/566.4 [M+H]⁺ (LC-MS 2).

Step 154.2{3-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-aceticacid methyl ester

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate E and the product from step 154.3.t_(R): 1.26 min (LC-MS 2); ESI-MS: 578.3/580.3 [M+H]⁺ (LC-MS 2).

Step 154.3[4-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid methyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 154.4. The residuewas purified by flash chromatography (hexane/EtOAc). t_(R): 1.07 min(LC-MS 2); R_(f): 0.47 (hexane/EtOAc 2:1).

Step 154.3 (3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester

A solution of 3-bromo-4-methoxyphenylacetic acid (7.5 g, 30.6 mmol),MeOH (24 mL) and H₂SO₄ (0.8 mL) was stirred at 75° C. for 17 h. Thereaction mixture was concentrated. The residue was poured into H₂O andextracted with CH₂Cl₂. The organic layer was washed with brine, dried(NaSO₄), filtered and concentrated to afford the title compound. t_(R):0.99 min (LC-MS 2).

Example 1552-{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N,N-dimethyl-acetamide

The title compound was prepared in analogy to the procedure describedfor intermediate F but using the product from example 162 anddimethylamine (2M in THF). The reaction was performed at rt. Thereaction mixture was diluted with EtOAc and extracted with H₂O. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The residuewas purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) togive the title compound. t_(R): 1.16 min (LC-MS 2); ESI-MS: 595.4/597.3[M+H]⁺ (LC-MS 2).

Example 1565-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((S)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 156.1. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→0:100). t_(R):1.18 min (LC-MS 2); ESI-MS: 568.5/570.5 [M+H]⁺ (LC-MS 2).

Step 156.12-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-((S)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

A solution of the product from step 156.2 (850 mg, 1.3 mmol) in DMF (5mL) was stirred at 100° C. for 1 h. The reaction mixture was cooled tort, diluted with EtOAc and extracted with a saturated aqueous NaHCO₃solution. The organic layer was washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography (hexane/EtOAc, 100:0→60:40) to afford the title compound.t_(R): 1.19/1.21 min (LC-MS 2); ESI-MS: 508.2/510.2/521.3 [M+H]⁺ (LC-MS2).

Step 156.22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((S)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid benzotriazol-1-yl ester

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 156.3. The reactionwas performed at rt for 1 h. The reaction mixture was diluted with EtOAcand extracted with a saturated aqueous NaHCO₃ solution. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by flash chromatography (heptane/EtOAc,100:0→60:40). t_(R): 1.45 min (LC-MS 2); ESI-MS: 643.3/645.1/647.2[M+H]⁺ (LC-MS 2).

Step 156.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((S)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 156.4. The reaction wasperformed in EtOH at rt for 20 h. EtOH was removed and at 0° C. wasadded a citric acid solution, extracted with CH₂Cl₂, dried (Na₂SO₄),filtered and concentrated. t_(R): 1.25 min (LC-MS 2); ESI-MS:526.1/528.1/530.2 [M+H]⁺ (LC-MS 2).

Step 156.42-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-((S)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 156.5 and5-chloro-2-methylaniline. The product was purified by flashchromatography (heptane/EtOAc, 100:0→70:30). t_(R): 1.44/1.47 min (LC-MS2); ESI-MS: 554.2/556.3/558.3 [M+H]⁺ (LC-MS 2).

Step 156.52-Bromo-5-[(S)-(4-chloro-phenyl)-hydroxy-methyl]-1-((S)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate B but using the product from step 156.6. The reactionwas quenched with a 1M aqueous NH₄Cl solution and extracted with EtOAc.The organic layer was dried (Na₂SO₄), filtered and concentrated. Theproduct was purified by flash chromatography (heptane/EtOAc,100:0→60:40). t_(R): 1.11 min (LC-MS 2); ESI-MS: 431.2/433.2 [M+H]⁺(LC-MS 2).

Step 156.62-Bromo-1-((S)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylic acidethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate A but using the product from step 156.7. The productwas purified by flash chromatography (hexane/EtOAc, 100:0→1:1). t_(R):0.76 min (LC-MS 2); ESI-MS: 291.2/293.2 [M+H]⁺ (LC-MS 2).

Step 156.7 1-((S)-2-Methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 111.9 but using (S)-1-methoxy-2-propylamine. The reactionmixture was concentrated and purified by flash chromatography(hexane/EtOAc, 100:0→0:100). t_(R): 0.59 min (LC-MS 2); ESI-MS: 213.2[M+H]⁺ (LC-MS 2).

Example 1572-{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-N-methyl-acetamide

The title compound was prepared in analogy to the procedure describedfor intermediate F but using the product from example 162 andmethylamine (2M in THF). The reaction was performed at rt. The reactionmixture was diluted with EtOAc and extracted with H₂O. The organic layerwas dried (Na₂SO₄), filtered and concentrated. The residue was purifiedby preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) to givethe title compound. t_(R): 1.11 min (LC-MS 2); ESI-MS: 581.3/583.3[M+H]⁺ (LC-MS 2).

Example 1585-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 158.1 and intermediate W.The reaction mixture was concentrated and diluted with a saturatedaqueous NH₄Cl solution and extracted with EtOAc. The organic layer wasdried (Na₂SO₄), filtered and concentrated. The product was purified byflash chromatography (CH₂Cl₂/MeOH, 99:1→94:6). The residue was purifiedby preparative chromatography (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) togive the title compound. t_(R): 1.06 min (LC-MS 2); ESI-MS: 554.2/556.2[M+H]⁺ (LC-MS 2); R_(f): 0.42 (CH₂Cl₂/MeOH 9:1).

Step 158.12-Bromo-5-(5-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 158.2. The reactionwas concentrated and diluted with a saturated aqueous NH₄Cl solution andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The product was purified by flash chromatography(CH₂Cl₂/MeOH, 99:1→96:4). The residue was purified by preparativechromatography (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) to givethe title compound. t_(R): 0.95 min (LC-MS 2); ESI-MS: 481.1/483.1/485.1[M+H]⁺ (LC-MS 2); R_(f): 0.33 (CH₂Cl₂/MeOH 9:1).

Step 158.22-Bromo-5-[(5-chloro-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 158.3. The reaction wasconcentrated and diluted with a saturated aqueous NH₄Cl solution andextracted with CH₂Cl₂/MeOH 9:1. The organic layer was dried (Na₂SO₄),filtered and concentrated. The product was used without furtherpurification. t_(R): 0.97 min (LC-MS 2); ESI-MS: 499.1/501.1/503.1[M+H]⁺ (LC-MS 2).

Step 158.32-Bromo-5-[(5-chloro-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-chloro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 3-amino-5-chloropyridin-2-ol.The reaction mixture was quenched with a saturated aqueous NaHCO₃solution and extracted with EtOAc. The organic layer was washed with asaturated aqueous NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The product was purified by flash chromatography(CH₂Cl₂/MeOH, 99:1→97:3). t_(R): 1.15-1.18 min (LC-MS 2); ESI-MS:527.1/529.1/531.1 [M+H]⁺ (LC-MS 2); R_(f): 0.41 (CH₂Cl₂/MeOH 9:1).

Example 1592-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 101.1 and intermediate U.The reaction was performed at 110° C. for 30 min. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 92.7:7.2). The residuewas purified by preparative chromatography (Waters Sun Fire C18, 30×100mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 20-60% in20 min) to give the title compound. t_(R): 0.94 min (LC-MS 2); ESI-MS:540.2/542.2 [M+H]⁺ (LC-MS 2); R_(f): 0.10 (CH₂Cl₂/MeOH 92.7:7.5); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.08 (s, 1H), 7.89 (d, 1H), 7.47 (d, 1H),7.42-7.38 (m, 2H), 7.32-7.25 (m, 2H), 7.06 (s, 2H), 6.68 (s, 1H),4.10-4.04 (m, 1H), 3.81 (s, 3H), 3.42 (s, 3H), 1.31 (d, 3H), 0.50 (d,3H).

Example 1604-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 100 (Column: Chiralpak iA, 20×250 mm.Flow 13 mL/min. hexane/EtOH 50:50). t_(R): 29.2 min (Column: ChiralpakiA, 4.6×250 mm. Flow 1 mL/min. hexane/EtOH 50:50).

Example 1614-[(R)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 100 (Column: Chiralpak iA, 20×250 mm.Flow 13 mL/min. hexane/EtOH 50:50). t_(R): 6.4 min (Column: ChiralpakiA, 4.6×250 mm. Flow 1 mL/min. hexane/EtOH 50:50).

Example 162{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-aceticacid

The title compound was prepared in analogy to the procedure describedfor step 64.1 but using the product from example 165. The reaction wasperformed at rt. The reaction mixture was diluted with EtOAc andextracted with 5% citric acid. The organic layer was dried (Na₂SO₄),filtered and concentrated. t_(R): 1.12 min (LC-MS 2); ESI-MS:568.2/570.3 [M+H]⁺ (LC-MS 2).

Example 163(R)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 158. (Column: Chiralpak AS-H, 30×250mm. Flow 80 mL/min. scCO₂/MeOH 70:30). t_(R): 5.11 min (Column:Chiralpak AS-H, 4.6×250 mm. Flow 3 mL/min. scCO₂/MeOH 70:30).

Example 164(S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 158. (Column: Chiralpak AS-H, 30×250mm. Flow 80 mL/min. scCO₂/MeOH 70:30). t_(R): 1.69 min (Column:Chiralpak AS-H, 4.6×250 mm. Flow 3 mL/min. scCO₂/MeOH 70:30).

Example 165{3-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-phenyl}-aceticacid methyl ester

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate G and the product from step 154.3.t_(R): 1.21 min (LC-MS 2); ESI-MS: 582.3/584.3 [M+H]⁺ (LC-MS 2).

Example 1664-[(R)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 79. (Column: Chiralpak AD-H, 30×250mm. Flow 100 mL/min. scCO₂/EtOH 70:30). t_(R): 3.50 min (Column:Chiralpak AD-H, 4.6×250 mm. Flow 3 mL/min. scCO₂/EtOH 70:30).

Example 1674-[5-(3-Chloro-4-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 167.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After the purification bypreparative HPLC, the residue was purified by preparative TLC (EtOAc) togive the title compound. t_(R): 1.08 min (LC-MS 2); ESI-MS: 551.3 [M+H]⁺(LC-MS 2).

Step 167.14-[2-Bromo-5-(3-chloro-4-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 144.3 but using the product from step 167.2. The reaction wasperformed at 80° C. for 5 h. The product was purified by flashchromatography (heptanes/EtOAc, 1:1→0:100) to give the title compound.t_(R): 1.09 min (LC-MS 2); ESI-MS: 491.1/493.1 [M+H]⁺ (LC-MS 2).

Step 167.22-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 167.3. t_(R): 1.09 min(LC-MS 2); ESI-MS: 509.0 [M+H]⁺ (LC-MS 2).

Step 167.32-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 167.4 and3-chloro-4-fluoroaniline. The mixture was extracted with a saturatedaqueous NaHCO₃ solution. The organic layers were dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (hexane/EtOAc, 100:0→60:40). t_(R): 1.27 min (LC-MS 2);ESI-MS: 537.2/539.2 [M+H]⁺ (LC-MS 2).

Step 167.42-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate B but using intermediate A and4-cyano-3-fluorobenzaldehyde. The product was purified by flashchromatography (hexane/EtOAc, 100:0→0:100). The residue was thentriturated in Et₂O to give the title compound as white foam. t_(R): 1.03min (LC-MS 2); ESI-MS: 410.1/412.1 [M+H]⁺ (LC-MS 2).

Example 168(R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 27. (Column: Chiralpak OD-H, 30×250mm. Flow 100 mL/min. scCO₂/EtOH 65:35). t_(R): 2.39 min (Column:Chiralpak OD-H, 4.6×250 mm. Flow 3 mL/min. scCO₂/EtOH 60:40).

Example 169(S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 27. (Column: Chiralpak OD-H, 30×250mm. Flow 100 mL/min. scCO₂/EtOH 65:35). t_(R): 1.77 min (Column:Chiralpak OD-H, 4.6×250 mm. Flow 3 mL/min. scCO₂/EtOH 60:40).

Example 1704-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,56-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carbonitrile

To a solution of the product from step 121.1 (115 mg, 0.2 mmol) in DMF(2 mL) was added Pd(PPh₃)₂ (73 mg, 0.06 mmol) and Zn(CN)₂ (17 mg, 0.15mmol) and the mixture was stirred at 100° C. for 16 h. The reactionmixture was diluted with EtOAc and extracted with H₂O. The organic layerwas dried (Na₂SO₄), filtered and concentrated. The residue wastriturated in acetonitrile and MeOH and filtered. The mother liquor wasconcentrated. The residue was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 50-90% in 16 min) to give the title compound. t_(R): 1.21min (LC-MS 2); ESI-MS: 533.2/535.2 [M+H]⁺ (LC-MS 2).

Example 1715-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-5-methoxy-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step W1 but using the product from step 96.1. The reaction wasperformed at 70° C. for 24 h. The reaction mixture was diluted withEtOAc and extracted with H₂O. The organic layer was dried (Na₂SO₄),filtered and concentrated. The product was purified by SFCchromatography then by preparative HPLC (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 25-45% in 16min) to give the title compound. t_(R): 1.25 min (LC-MS 2); ESI-MS:555.3/557.3 [M+H](LC-MS 2).

Example 1725-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-5-methoxy-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 171 but using the product from step 121.1. t_(R): 1.28 min(LC-MS 2); ESI-MS: 551.3/553.3 [M+H]⁺ (LC-MS 2).

Example 1733-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 173.1 and intermediate Q.The product was purified by SFC chromatography (Column DEAP, 250×30 mm,5 μm, flow 100 mL/min, grad 23-28% over 6 min) to give the titlecompound. t_(R): 1.08 min (LC-MS 2); ESI-MS: 553.3/555.2 [M+H]⁺ (LC-MS2).

Step 173.14-Methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide

The title compound was prepared in analogy to the procedure describedfor intermediate U but using 3-bromo-4-methoxybenzamide. The reactionwas performed at 100° C. for 17 h. ESI-MS: 278.1 [M+H]⁺ (MS 1).

Example 1743-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 173.1 and intermediate G.The reaction was performed at 80° C. for 3 h. After an aqueous workup,the product was purified by SFC chromatography (Column 2-EP, 250×30 mm,5 μm, flow 100 mL/min, grad 18-23% over 6 min) to give the titlecompound. t_(R): 1.06 min (LC-MS 2); ESI-MS: 553.3/555.2 [M+H]⁺ (LC-MS2).

Example 1753-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 173.1 and intermediate E.The reaction was performed at 80° C. for 3 h. After an aqueous workup,the product was purified by SFC chromatography (Column 2-EP, 250×30 mm,5 μm, flow 100 mL/min, grad 18-23% over 6 min) to give the titlecompound. t_(R): 1.06 min (LC-MS 2); ESI-MS: 553.3/555.2 [M+H]⁺ (LC-MS2).

Example 1763-[5-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 207 but using the product from step 173.1 and intermediateJ. The reaction was performed at 110° C. for 10 min under microwaveirradiation. The residue was purified by preparative chromatography(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min) to give the title compound.t_(R): 1.16 min (LC-MS 2); ESI-MS: 563.2/565.2 [M+H]⁺ (LC-MS 2).

Example 1775-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 158.1 and intermediate Z.The residue was purified by flash chromatography (CH₂Cl₂/MeOH,92.5:7.5), then by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1% TFA in water,B=CH₃CN). t_(R): 0.92 min (LC-MS 2); ESI-MS: 540.3/542.3 [M+H]⁺ (LC-MS2); R_(f)=0.13 (CH₂Cl₂/MeOH, 92.5:7.5); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm12.21 (s, 1H), 8.25-8.03 (m, 1H), 7.60-7.20 (m, 7H), 6.70 (s, 1H),4.13-4.03 (m, 1H), 3.95-3.72 (m, 3H), 2.84 (s, 3H), 1.31 (d, 3H), 0.50(d, 3H).

Example 1785-[6-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 178.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction was performed at110° C. for 30 min. The product was purified by flash chromatography(CH₂Cl₂/MeOH, 95:5). The residue was purified by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-60%B in 20 min; A=0.1% TFA in water, B=CH₃CN) to afford the title compound.t_(R): 0.93 min (LC-MS 2); ESI-MS: 552.3/554.3 [M+H]⁺ (LC-MS 2);R_(f)=0.17 (CH₂Cl₂/MeOH, 95:5); ¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.48 (s,1H), 7.71 (s, 1H), 7.50-7.40 (m, 2H), 7.35-7.20 (m, 2H), 6.10 (s, 1H),4.15-4.05 (m, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.22 (s, 3H), 3.15 (s,3H), 1.29 (d, 3H), 0.51 (d, 3H).

Step 178.15-[2-Bromo-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor example E but using the product from step 178.2. After extraction,the residue was triturated in EtOAc to afford the title compound. t_(R):0.92/0.95 min (LC-MS 2); ESI-MS: 492.2/494.2 [M+H]⁺ (LC-MS 2).

Step 178.22-Bromo-5-[(4-chloro-phenyl)-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 178.3. After extraction, theresidue was triturated in Et₂O to afford the title compound. t_(R): 0.94min (LC-MS 2); ESI-MS: 510.2/512.2 [M+H]⁺ (LC-MS 2).

Step 178.32-Bromo-5-[(4-chloro-phenyl)-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and the product from step 178.4.The reaction mixture was stirred at −10° C. for 18 h. After extraction,the residue was purified by flash chromatography (hexane/EtOAc, 60:40).t_(R): 1.13 min (LC-MS 2); ESI-MS: 538.2/540.2 [M+H]⁺ (LC-MS 2),R_(f)=0.22 (hexane/EtOAc, 4:6).

Step 178.4 5-Amino-1,3-dimethyl-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor step 100.4 but using the product from step 178.5. The reaction wasperformed at rt for 67.5 h. The residue was purified by flashchromatography (CH₂Cl₂/MeOH/NH₃, 99:1:1→97:3:1). t_(R): 0.31 min (LC-MS2); ESI-MS: 156.2 [M+H]⁺ (LC-MS 2); R_(f)=0.47 (CH₂Cl₂/MeOH, 9:1).

Step 178.5 1,3-Dimethyl-5-nitro-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor step 100.5 but using 5-nitrouracil. The reaction was performed at rtfor 20 h. The reaction mixture was concentrated and triturated inCH₂Cl₂. The resulting suspension was filtered and the solid was purifiedby flash chromatography (CH₂Cl₂/MeOH, 94:6). t_(R): 0.41 min (LC-MS 2);ESI-MS: 186.1 [M+H]⁺ (LC-MS 2); R_(f)=0.55 (CH₂Cl₂/MeOH, 9:1).

Example 1795-[6-(4-Chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 178.1 and intermediate W.The reaction was performed at 110° C. for 30 min. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 95:5). The residue waspurified by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm.Flow: 30 mL/min. Gradient 30-70% B in 20 min; A=0.1% TFA in water,B=CH₃CN) to afford the title compound. t_(R): 1.01 min (LC-MS 2);ESI-MS: 565.4/567.3 [M+H]⁺ (LC-MS 2); R_(f)=0.19 (CH₂Cl₂/MeOH, 95:5).

Example 1805-[2-(2-Amino-4-methoxy-pyrimidin-5-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-d]imidazol-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-dione

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 178.1 and intermediate U.The reaction was performed at 110° C. for 30 min. The product waspurified by flash chromatography (CH₂Cl₂/MeOH, 92.5:7.5). The residuewas purified by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm.Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1% TFA in water,B=CH₃CN), then the residue was triturated in Et₂O to afford the titlecompound. t_(R): 0.81 min (LC-MS 2); ESI-MS: 537.3/538.3 [M+H]⁺ (LC-MS2); R_(f)=0.28 (CH₂Cl₂/MeOH, 92.5:7.5).

Example 1815-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 181.1. The residue waspurified by flash chromatography (hexane/EtOAc, 100:0→20:80). t_(R):1.19 min (LC-MS 2); ESI-MS: 536.4/538.2 [M+H]⁺ (LC-MS 2); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.52 (s, 1H), 7.41-7.21 (m, 6H), 6.36 (s, 1H),4.04 (s, 3H), 4.01 (s, 3H), 2.05 (s, 3H), 1.28 (m, 3H), 0.59 (m, 3H).

Step 181.12-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-cyclopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate E but using the product from step 181.2. The reactionmixture was diluted with EtOAc and extracted with a saturated aqueousNaHCO₃ solution. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified by flashchromatography (heptane/EtOAc, 100:0→1:1). t_(R): 1.23 min (LC-MS 2);ESI-MS: 576.2/478.1/480.1 [M+H]⁺ (LC-MS 2).

Step 181.22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 156.3 but using the product from step 181.3. t_(R): 1.27 in(LC-MS 2); ESI-MS: 494.2/496.2/498.2 [M+H]⁺ (LC-MS 2).

Step 181.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-chloro-phenyl)-methyl]-1-cyclopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step AN2 and5-chloro-1-methylaniline. The reaction was extracted with a saturatedaqueous NaHCO₃ solution, washed with brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 100:0→1:1). t_(R): 1.48 min (LC-MS 2); ESI-MS:522.1/524.1/526.0 [M+H]⁺ (LC-MS 2).

Example 1824-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 182.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction mixture wasdiluted with EtOAc and extracted with a saturated aqueous NaHCO₃solution. The organic layer was washed with brine, dried (Na₂SO₄),filtered and concentrated. The product was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 50-75% in 25 min). The residue was purified bypreparative TLC (CH₂Cl₂/MeOH, 9:1). The residue was lyophilized indioxane. The residue was triturated in Diisopropylether to afford thetitle compound. t_(R): 1.07 min (LC-MS 2); ESI-MS: 547.3/549.3 [M+H]⁺(LC-MS 2); R_(f)=0.52 (CH₂Cl₂/MeOH, 9:1).

Step 182.14-[2-Bromo-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 144.3 but using the product from step 182.2. The reaction wasperformed at 80° C. for 3 h. The residue was diluted with EtOAc andextracted with a saturated aqueous NaHCO₃ solution/H₂O. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The product was purified by flash chromatography (heptanes/EtOAc,1:1→10:90). The residue was lyophilized in dioxane to afford the titlecompound. t_(R): 1.11 min (LC-MS 2); ESI-MS: 487.1/489.1 [M+H]⁺ (LC-MS2); R₁=0.22 (hexane/EtOAc, 1:2).

Step 182.22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 182.3. t_(R): 1.13 min(LC-MS 2); ESI-MS: 505.0/507.2/509.0 [M+H]⁺ (LC-MS 2).

Step 182.32-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 182.4. The resulting mixturewas extracted with a saturated aqueous NaHCO₃ solution. The organiclayers were washed with brine, dried (MgSO₄), filtered and concentrated.The crude product was purified by flash chromatography (heptane/EtOAc,95:5→80:20). t_(R): 1.30 min (LC-MS 2); ESI-MS: 533.1/535.2 [M+H](LC-MS2), R_(f)=0.42 (hexane/EtOAc, 1:1).

Step 182.42-Bromo-5-[(4-cyano-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate B using the product from step 182.5. The resultingsolid was purified by flash chromatography (heptane/EtOAc, 80:20→60:40).t_(R): 1.01 min (LC-MS 2); ESI-MS: 406.1/408.0 [M+H]⁺ (LC-MS 2).

Step 182.5 4-Formyl-3-methyl-benzonitrile

To a solution of 4-bromo-3-methylbenzonitrile (20 g, 102 mmol) in THF(500 mL) at −100° C. was slowly added a solution of n-Buli 1.6M inhexanes (70 mL, 112 mmol). DMF (11 mL, 143 mmol) was then added and themixture was allowed to warm to −50° C. over 30 min. The reaction mixturewas quenched with brine. The reaction mixture was diluted with EtOAc andextracted with brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(hexane/EtOAc, 80:20) the residue was triturated in Et₂O/hexane 90:10 toafford the title compound. t_(R): 0.86 min (LC-MS 2); R_(f)=0.40(hexane/EtOAc, 8:2).

Example 1834-[5-(3-Chloro-2-fluoro-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 182.1 and2-methoxyphenylboronic acid. The reaction mixture was diluted with EtOAcand extracted with a saturated aqueous NaHCO₃ solution. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The product was purified by preparative HPLC (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile50-75% in 25 min). t_(R): 1.13 min (LC-MS 2); ESI-MS: 515.3/516.4 [M+H]⁺(LC-MS 2).

Example 1845-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates G and W. The product was purifiedby preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) toprovide the title compound. t_(R): 1.26 min (LC-MS 2); ESI-MS:555.3/557.1 [M+H]⁺ (LC-MS 2).

Example 1855-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates Q and W. The product was purifiedby preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-70% in 16 min) toprovide the title compound. t_(R): 1.25 min (LC-MS 2); ESI-MS:555.3/557.1 [M+H]⁺ (LC-MS 2).

Example 1863-[5-(5-Chloro-2-methyl-phenyl)-6-(4-cyano-2-methyl-phenyl)-6-(4-cyano-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 186.1 and intermediate M.The mixture was diluted in EtOAc and extracted with a saturated aqueousNaHCO₃ solution. The organic layers were washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified bypreparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-75% in 25 min) toprovide the title compound. t_(R): 1.05 min (LC-MS 2); ESI-MS:582.2/584.2 [M+H]⁺ (LC-MS 2).

Step 186.14-[2-Bromo-5-(5-chloro-2-methyl-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 182.1 but using the product from step 186.2. The product waspurified by flash chromatography (heptanes/EtOAc, 7:3→3:7) to afford thetitle compound. t_(R): 1.10 min (LC-MS 2); ESI-MS: 483.1/485.0 [M+H]⁺(LC-MS 2); R_(f)=0.69 (EtOAc).

Step 186.22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 186.3. t_(R): 1.16 min(LC-MS 2); ESI-MS: 501.2/503.3 [M+H]⁺ (LC-MS 2).

Step 186.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 182.4. The reaction mixturewas stirred at rt for 4 days. The mixture was extracted with a saturatedaqueous NaHCO₃ solution. The organic layers were dried (Na₂SO₄),filtered and concentrated. The residue was purified by flashchromatography (hexane/EtOAc, 95:5→80:20) to afford the title compound.t_(R): 1.33 min (LC-MS 2); ESI-MS: 529.2/531.1 [M+H]⁺ (LC-MS 2).

Example 1874-[5-(5-Chloro-2-methyl-phenyl)-2-(1-ethyl-5-methoxy-2-oxo-1,2-dihydro-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate H and the product from step 187.1.The reaction was performed at 110° C. for 1 h. The reaction mixture wasdissolved in EtOAc and extracted with a saturated aqueous NaHCO₃solution. The organic layer was washed with brine, dried (Na₂SO₄),filtered and concentrated. The residue was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min) to give the title compound.t_(R): 0.99 min (LC-MS 2); ESI-MS: 542.2/544.3 [M+H]⁺ (LC-MS 2),R_(f)=0.23 (CH₂Cl₂/MeOH, 9:1); ¹H-NMR (DMSO-d₆, 400 MHz)

(m, 8H), 7.58-7.41 (m, 3H), 7.28-7.03 (m, 2H), 6.69 (s, 1H), 6.52 (s,1H), 4.19-4.05 (m, 1H), 4.00-3.86 (m, 2H), 3.64 (s, 3H), 1.97-1.83 (m,3H), 1.36-1.21 (m, 6H), 0.60-0.40 (m, 3H).

Step 187.1 (1-ethyl-5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)boronic acid

The title compound was prepared in analogy to the procedure describedfor intermediate S but using the product from step 187.2. The reactionwas performed at 80° C. for 2 h. The reaction mixture was filtered overcelite and concentrated. The residue was purified by flashchromatography (CH₂Cl₂/MeOH, 90:10) to afford the title compound. t_(R):0.40 min (LC-MS 2); ESI-MS: 198.1 [M+H]⁺ (LC-MS 2).

Step 187.2 1-Ethyl-4-iodo-5-methoxy-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure describedfor step 100.5 but using the product from step 187.3 and ethyl iodide.The reaction was stirred at rt for 30 min. The reaction mixture wasquenched by addition of a saturated aqueous NaHCO₃ solution, andextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered,and concentrated. The residue was purified by flash chromatography(CH₂Cl₂/MeOH, 99:1→97:3) to afford the title compound. t_(R): 0.69 min(LC-MS 2); ESI-MS: 280.0 [M+H]⁺ (LC-MS 2); R_(f)=0.60 (CH₂Cl₂/MeOH,9:1).

Step 187.3 4-Iodo-5-methoxy-1H-pyridin-2-one

A solution of the product from step 187.4 (440 mg, 1.2 mmol) and TFA(457 μL, 5.9 mmol) in CH₂Cl₂ (5 mL) was stirred at rt for 10 min. Thereaction mixture was quenched with a saturated aqueous NaHCO₃ solution.The resulting suspension was filtered and the solid dried to afford thetitle compound. t_(R): 0.55 min (LC-MS 2); ESI-MS: 252.0 [M+H]⁺ (LC-MS2).

Step 187.4 4-Iodo-5-methoxy-2-(4-methoxy-benzyloxy)-pyridine

To a solution of 4-methoxybenzyl alcohol (342 mg, 2.1 mmol) in DMF (5mL) at 0° C. was added protionwise NaH (108 mg, 2.5 mmol) and themixture was stirred for 30 min. The product from step 187.5 (545 mg, 2.1mmol) was added dropwise and the mixture was stirred at 80° C. for 5min. The reaction mixture was quenched by addition of a saturatedaqueous NaHCO₃ solution, and extracted with EtOAc. The organic layer wasdried (Na₂SO₄), filtered, and concentrated. The residue was purified byflash chromatography (heptane/EtOAc, 98:2→95:5) to afford the titlecompound. t_(R): 1.28 min (LC-MS 2); ESI-MS: 372.1 [M+H]⁺ (LC-MS 2);R_(f)=0.28 (heptane/EtOAc, 9:1).

Step 187.5 2-Fluoro-4-iodo-5-methoxy-pyridine

A solution of the product from step 187.6 (730 mg, 3.0 mmol), K₂CO₃ (1.3g, 9.2 mmol) and methyl iodide (573 μL, 9.2 mmol) in DMF (3 mL) wasstirred at 60° C. for 1 h. The reaction mixture was quenched with asaturated aqueous NaHCO₃ solution and extracted with EtOAc. The organiclayer was dried (Na₂SO₄), filtered and concentrated. The product waspurified by flash chromatography (hexane/EtOAc, 97.5:2.5→95:5t) toprovide the title compound. t_(R): 0.94 min (LC-MS 2); R_(f)=0.32(heptane/EtOAc, 9:1).

Step 187.6 6-Fluoro-4-iodo-pyridin-3-ol

A solution of the product from step 187.7 (886 mg, 3.1 mmol) and HCl 6M(3.1 mL, 18.8 mmol) in THF (5 mL) was stirred at 60° C. for 1 h. Thereaction mixture was quenched with a saturated aqueous NaHCO₃ solutionand extracted with EtOAc. The organic layer was dried (Na₂SO₄), filteredand concentrated. The product was used without further purification.t_(R): 0.75 min (LC-MS 2); ESI-MS: 240.1 [M+H]⁺ (LC-MS 2).

Step 187.7 2-Fluoro-4-iodo-5-methoxymethoxy-pyridine

To a solution of the product from step 187.8 (1 g, 6.4 mmol) in THF (20mL) at −78° C. was added dropwise t-Buli 1.7M in hexanes (7.5 mL, 12.7mmol) and the mixture was stirred for 30 min. Then iodine (4.2 g, 9.5mmol) in THF (10 mL) was added. The mixture was allowed to warm up andstirred at rt for 1 h. The reaction mixture was quenched with H₂O andextracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified by flashchromatography (heptane/EtOAc, 100:0→95:5) to afford the title compound.t_(R): 0.97 min (LC-MS 2); ESI-MS: 284.0 [M+H]⁺ (LC-MS 2); R_(f)=0.31(heptane/EtOAc, 9:1).

Step 187.8 2-Fluoro-5-methoxymethoxy-pyridine

To a solution of 5-fluoro-2-hydroxypyridine (4.9 g, 43.2 mmol) in DMF(50 mL) at 0° C. was added protionwise NaH (2.3 g, 52.2 mmol) and themixture was stirred at 0° C. for 10 min. Chloromethyl methyl ether (3.6mL, 47.5 mmol) was added dropwise and the mixture was stirred at rt for30 min. The reaction mixture was quenched by addition of water, andextracted with EtOAc. The organic layer was washed with brine, dried(Na₂SO₄), filtered, and concentrated. The residue was purified by flashchromatography (heptane/EtOAc, 97.5:2.5→92.5:7.5) to afford the titlecompound. t_(R): 0.71 min (LC-MS 2); ESI-MS: 158.1 [M+H]⁺ (LC-MS 2);R_(f)=0.33 (heptane/EtOAc, 9:1).

Example 1884-[5-(5-Chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 186.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction mixture wasdiluted in EtOAc and extracted with a saturated aqueous NaHCO₃ solution.The organic layer was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The product was purified by preparative TLC (EtOAc), thenby preparative TLC (CH₂Cl₂/MeOH, 9:1). The residue was purified bypreparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 50-75% in 13 min) to givethe title compound. t_(R): 1.09 min (LC-MS 2); ESI-MS: 543.4/545.2[M+H]⁺ (LC-MS 2), R_(f): 0.24 (EtOAc).

Example 1893-[(R)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 23. (Column: AD-H, 20×200 mm. Flow 7mL/min. n-heptane/EtOH 50:50). t_(R): 9.1 min (Column: AD-H, 4.6×250 mm.Flow 1 mL/min. n-heptane/EtOH 50:50).

Example 1903-[(S)-5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was obtained after preparative chiral HPLC separationof the racemic product of example 23. (Column: AD-H, 20×200 mm. Flow 7mL/min. n-heptane/EtOH 50:50). t_(R): 4.3 min (Column: AD-H, 4.6×250 mm.Flow 1 mL/min. n-heptane/EtOH 50:50).

Example 1914-[5-(5-Chloro-2-methyl-phenyl)-3-isopropyl-2-(2-methoxy-phenyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 186.1 and2-methoxyphenylboronic acid. The reaction mixture was diluted in EtOAcand extracted with a saturated aqueous NaHCO₃ solution. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The residue was purified by preparative HPLC (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile40-85%) to give the title compound. t_(R): 1.13/1.16 min (LC-MS 2);ESI-MS: 511.3/513.4 [M+H]⁺ (LC-MS 2), R_(f): 0.57 (EtOAc).

Example 1922-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates G and U. The reaction wasperformed at 110° C. The residue was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 25-45% in 16 min) to give the title compound.t_(R): 1.07 min (LC-MS 2); ESI-MS: 527.2/529.2 [M+H]⁺ (LC-MS 2).

Example 1932-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates Q and U. The reaction wasperformed at 110° C. The residue was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 25-45% in 16 min) to give the title compound.t_(R): 1.10 min (LC-MS 2); ESI-MS: 527.2/529.3 [M+H]⁺ (LC-MS 2).

Example 1943-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate Q and5-cyano-2-methoxyphenylboronic acid. The reaction was performed at 110°C. The residue was purified by SFC chromatography (Column 2-EP, 250×30mm, 5 μm, flow 100 mL/min, grad 20-25% over 6 min) to give the titlecompound. t_(R): 1.24 min (LC-MS 2); ESI-MS: 535.2/537.2 [M+H]⁺ (LC-MS2).

Example 1955-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates Q and O. The reaction wasperformed at 110° C. The residue was purified by SFC chromatography(Column 2-EP, 250×30 mm, 5 μm, flow 100 mL/min, grad 17-22% over 6 min).The residue was purified by preparative HPLC (Column: Sunfire C18,30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 50-70% B in 16 min; A=0.1%TFA in water, B=CH₃CN). t_(R): 1.13 min (LC-MS 2); ESI-MS: 623.3/625.3[M+H]⁺ (LC-MS 2).

Example 1965-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate W and the product from step 101.1.The reaction was performed at 110° C. The residue was purified by flashchromatography (CH₂Cl₂/MeOH, 95:5). The residue was purified bypreparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min.Gradient 30-70% B in 20 min; A=0.1% TFA in water, B=CH₃CN). The residuewas purified by SFC chromatography (Column 2-EP, 250×30 mm, 5 μm, flow100 mL/min, grad 13-18% over 11 min). t_(R): 1.13 min (LC-MS 2); ESI-MS:568.3/570.3 [M+H]⁺ (LC-MS 2); R_(f)=0.15 (CH₂Cl₂/MeOH, 95:5); ¹H-NMR(DMSO-d₆, 400 MHz) δ ppm 8.19 (s, 1H), 7.89 (d, 1H), 7.47 (d, 1H),7.45-7.35 (m, 2H), 7.30-7.20 (m, 2H), 6.68 (s, 1H), 4.13-4.03 (m, 1H),3.87 (s, 3H), 3.42 (s, 3H), 3.16 (s, 6H), 1.31 (d, 3H), 0.50 (d, 3H).

Example 1973-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediates Q and M. The reaction wasperformed at 110° C. The residue was purified by preparative HPLC(Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 30-70%B in 16 min; A=0.1% TFA in water, B=CH₃CN). t_(R): 1.14 min (LC-MS 3);ESI-MS: 581.3/583.3 [M+H]⁺ (LC-MS 3).

Example 1985-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using intermediate Q and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction was performed at110° C. The residue was purified by SFC chromatography (Column Diol,250×30 mm, 5 μm, flow 100 mL/min, grad 22% over 7 min). t_(R): 1.22 min(LC-MS 2); ESI-MS: 542.2/544.2 [M+H]⁺ (LC-MS 2).

Example 1994-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 79 (Column: Chiralpak AD-H, 30×250 mm,Flow 100 mL/min, scCO₂/EtOH 70:30). t_(R): 4.73 min (Column: ChiralpakAD-H, 4.6×250 mm, Flow 3 mL/min, scCO₂/EtOH 70:30).

Example 2003-[5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 101.1 and intermediate M.The reaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were washed with water and brineand then dried (Na₂SO₄) and concentrated. The product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5). The residue was purifiedby preparative chromatography (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) togive the title compound. t_(R): 0.99 min (LC-MS 2); ESI-MS: 594.3/596.3[M+H]⁺ (LC-MS 2); R_(f): 0.15 (CH₂Cl₂/MeOH 92.5:7.5).

Example 2015-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-[2-(3-hydroxy-azetidin-1-yl)-4-methoxy-pyrimidin-5-yl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 101.1 and intermediateAE. The reaction mixture was diluted in EtOAc/water and extracted twicewith EtOAc. The combined organic extracts were washed with water andbrine and then dried (Na₂SO₄) and concentrated. The product was purifiedby flash chromatography (CH₂Cl₂/MeOH, 92.5:7.5). The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 20-60% in 20min) to give the title compound. t_(R): 0.96 min (LC-MS 2); ESI-MS:596.3/598.3 [M+H]⁺ (LC-MS 2); R_(f): 0.14 (CH₂Cl₂/MeOH 92.5:7.5).

Example 2025-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 101.1 and intermediate Z.The reaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were washed with water and brineand then dried (Na₂SO₄) and concentrated. The product was purified byflash chromatography (CH₂Cl₂/MeOH, 92.5:7.5). The residue was purifiedby preparative chromatography (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 30-60% in 20 min) togive the title compound. t_(R): 1.02 min (LC-MS 2); ESI-MS: 554.2/556.2[M+H]⁺ (LC-MS 2); R_(f): 0.15 (CH₂Cl₂/MeOH 92.5:7.5).

Example 203(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 159. (Column: Chiralpak IA, 30×250 mm.Flow 140 g/min. scCO2/(MeOH/DCM, 9:1+0.1% IPAm), 60:40). t_(R): 4.3 min(Column: Chiralpak IA, 4.6×250 mm. Flow 3 mL/min. scCO2/(MeOH/DCM,9:1+1% IPAm), 65:35).

Example 204(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 159. (Column: Chiralpak IA, 30×250 mm.Flow 140 g/min. scCO2/(MeOH/DCM, 9:1+0.1% IPAm), 60:40). t_(R): 3.1 min(Column: Chiralpak IA, 4.6×250 mm. Flow 3 mL/min. scCO2/(MeOH/DCM,9:1+1% IPAm), 65:35).

Example 205(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chlorophenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 37. (Column: Chiralpak IA, 30×250 mm.Flow 140 g/min. scCO2/MeOH, 72:28). t_(R): 4.35 min (Column: ChiralpakIA, 4.6×250 mm. Flow 3 mL/min. scCO2/MeOH, 70:30).

Example 206(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 37. (Column: Chiralpak IA, 30×250 mm.Flow 140 g/min. scCO2/MeOH, 72:28). t_(R): 3.22 min (Column: ChiralpakIA, 4.6×250 mm. Flow 3 mL/min. scCO2/MeOH, 70:30).

Example 2073-[6-(4-Chloro-phenyl)-5-(5-chloro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

To a solution of intermediate AF (75 mg, 0.16 mmol) in DME/Water/EtOH (1mL, 286 μL, 143 μL) were added intermediate M (72 mg, 0.32 mmol) andNa₂CO₃ (52 mg, 0.49 mmol). The mixture was degassed 5 min and thenPd(PPh₃)₂Cl₂ (12 mg, 0.02 mmol) was added. Te reaction mixture wasstirred under microwave irradiation at 120° C. for 20 min. EtOAc andwater were added and the phases were separated. The organic phase wasdried (Na₂SO₄), filtered and concentrated. The residue was purified bypreparative chromatography (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20 min) to givethe title compound. t_(R): 1.05 min (LC-MS 2); ESI-MS: 564.2/566.2[M+H]⁺ (LC-MS 2).

Example 2085-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the intermediate G and2,4-dimethoxypyrimidine-5-boronic acid. The reaction mixture was dilutedin EtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 30-70% in 16min) to give the title compound. t_(R): 1.17 min (LC-MS 2); ESI-MS:542.2/544.2 [M+H]⁺ (LC-MS 2).

Example 2093-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 209.1 and the intermediateM. The reaction mixture was diluted in EtOAc/water and extracted twicewith EtOAc. The combined organic extracts were combined, dried (Na₂SO₄)and concentrated. The residue was purified by preparative chiral SFCseparation of the racemic product of example 37. (Column: Diol, 30×250mm. Flow 100 mL/min. scCO2/MeOH, gradient MeOH 23-28% in 6 min). to givethe title compound. t_(R): 1.20 min (LC-MS 2); ESI-MS: 591.1/593.1[M+H]⁺ (LC-MS 2).

Step 209.1(R)-2-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic intermediate E. (Column: Chiralcel OD-H, 30×250 mm. Flow140 g/min. scCO2/MeOH, 70:30). t_(R): 5.1 min (Column: Chiralcel OD-H,4.6×250 mm. Flow 3 mL/min. scCO2/MeOH, 70:30).

Example 2105-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 207 but using the intermediate AG and2,4-dimethoxypyrimidine-5-boronic acid The reaction mixture was dilutedin EtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20min) to give the title compound. t_(R): 1.21 min (LC-MS 2); ESI-MS:524.2/526.1 [M+H]⁺ (LC-MS 2).

Example 2113-[5-(3-Chloro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 207 but using the intermediate AG and5-cyano-2-metoxyphenylboronic acid The reaction mixture was diluted inEtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20min) to give the title compound. t_(R): 1.24 min (LC-MS 2); ESI-MS:517.2/519.2 [M+H]⁺ (LC-MS 2).

Example 2124-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzoicacid

The title compound was prepared in analogy to the procedure describedfor example 1 but using the intermediate E and4-carboxy-2-methoxyphenylboronic acid. The reaction mixture was dilutedin EtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 50-100% in 16min) to give the title compound. t_(R): 1.14 min (LC-MS 2); ESI-MS:550.2/552.2 [M+H]⁺ (LC-MS 2).

Example 2136-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-1-isopropyl-2-[2-methoxy-5-(morpholine-4-carbonyl)-phenyl]-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 207 but using intermediate O and the product from step214.1. The reaction mixture was diluted in EtOAc/water and extractedtwice with EtOAc. The combined organic extracts were combined, dried(Na₂SO₄) and concentrated. The residue was purified by preparativechromatography (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20 min) to givethe title compound. t_(R): 1.21 min (LC-MS 2); ESI-MS: 619.3/621.4[M+H]⁺ (LC-MS 2).

Example 2146-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 207 but using the product from step 214.1 and2,4-dimethoxypyrimidine-5-boronic acid The reaction mixture was dilutedin EtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20min) to give the title compound. t_(R): 1.29 min (LC-MS 2); ESI-MS:538.2/540.2 [M+H]f (LC-MS 2).

Step 214.12-Bromo-6-(4-chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 64 but using the product from step 214.2. The reaction wasquenched with saturated NaHCO₃ then extracted twice with EtOAc. Thecombined organic extracts were combined, dried (Na₂SO₄) andconcentrated. The product was purified by flash chromatography(heptane/EtOAc, 9:1) to give the title compound. t_(R): 1.28 min (LC-MS2); ESI-MS: 478.2/480.1/482.1 [M+H]⁺ (LC-MS 2).

Step 214.22-Bromo-5-[(4-chloro-2-methyl-phenyl)-(3-chloro-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 214.3. The reaction mixturewas diluted in EtOAc/water and extracted twice with EtOAc. The combinedorganic extracts were combined, dried (Na₂SO₄) and concentrated to givethe title compound. t_(R): 1.28 min (LC-MS 2); ESI-MS: 496.1/498.1/500.2[M+H]⁺ (LC-MS 2).

Step 214.32-Bromo-5-[(4-chloro-2-methyl-phenyl)-(3-chloro-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 with the intermediate C and the 3-chloroaniline. Thereaction mixture was diluted in DCM/water and the phases were separated.The organic phase was dried (Na₂SO₄) and concentrated. The product waspurified by flash chromatography (heptane/EtOAc, 9:1) to give the titlecompound. t_(R): 1.47 min (LC-MS 2); ESI-MS: 524.0/526.0/528.2 [M+H]⁺(LC-MS 2).

Example 2153-[6-(4-Chloro-2-methyl-phenyl)-5-(3-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 207 but using the product from step 214.1 and5-cyano-2-methoxyphenylboronic acid The reaction mixture was diluted inEtOAc/water and extracted twice with EtOAc. The combined organicextracts were combined, dried (Na₂SO₄) and concentrated. The residue waspurified by preparative chromatography (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 35-100% in 20min) to give the title compound. t_(R): 1.29 min (LC-MS 2); ESI-MS:531.3/533.2 [M+H]⁺ (LC-MS 2).

Example 2164-[5-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-3-methoxy-benzonitrile

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediates E and S. The reaction mixture wasdiluted in EtOAc/water and extracted twice with EtOAc. The combinedorganic extracts were combined, dried (Na₂SO₄) and concentrated. Theresidue was purified by preparative chromatography (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile50-100% in 16 min) to give the title compound. t_(R): 1.23 min (LC-MS2); ESI-MS: 531.2/533.3 [M+H]⁺ (LC-MS 2).

Example 2173-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-4-methoxy-benzamide

The title compound was obtained after preparative chiral chromatographyseparation of the racemic example 11. (Column: Chiralcel OD, 30×250 mm,heptane/EtOH, 85:15+0.1% DEA). t_(R): 1.10/1.12 min (LC-MS 2); ESI-MS:607.3/609.3 [M+H]⁺ (LC-MS 2).

Example 2183-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-4-methoxy-benzamide

The title compound was obtained after preparative chiral chromatographyseparation of the racemic example 11. (Column: Chiralcel OD, 30×250 mm,heptane/EtOH, 85:15+0.1% DEA). t_(R): 1.10/1.12 min (LC-MS 2); ESI-MS:607.3/609.3 [M+H]⁺ (LC-MS 2).

Example 2194-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-(2-hydroxy-ethyl)-3-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate F and the product from step 219.1.The reaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were combined, dried (Na₂SO₄) andconcentrated. The residue was purified by SFC (Column: DEAP, 30×250 mm.Flow 100 mL/min. scCO2/MeOH, gradient of MeOH 20-25% in 6 min) t_(R):1.09/1.12 min (LC-MS 2); ESI-MS: 607.4/609.2 [M+H]⁺ (LC-MS 2).

Step 219.1 (4-((2-hydroxyethyl)carbamoyl)-2-methoxyphenyl)boronic acid

The title compound was prepared in analogy to the procedure describedfor Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid andethanolamine. The solvent was removed and then water and EtOAc wereadded. The phases were separated and the aqueous one was extracted twicewith EtOAc. The organics extracts were combined and dried (Na₂SO₄), andconcentrated. The residue was triturated in acetonitrile to give thetitle compound. t_(R): 0.42 min (LC-MS 2); ESI-MS: 240.1 [M+H]⁺ (LC-MS2).

Example 2204-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-3-methoxy-benzamide

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate F and product from step 220.1. Thereaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were combined, dried (Na₂SO₄) andconcentrated. The residue was purified by preparative chromatography(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 50-100% in 16 min). The residue was purified bySFC (Column: DEAP, 30×250 mm. Flow 100 mL/min. scCO₂/MeOH, gradient ofMeOH: 15 to 20% in 6 min). to give the title compound. t_(R): 1.25 min(LC-MS 2); ESI-MS: 605.4/607.3 [M+H]⁺ (LC-MS 2).

Step 220.1 (4-(isopropylcarbamoyl)-2-methoxyphenyl)boronic acid

The title compound was prepared in analogy to the procedure describedfor Intermediate K from 4-carboxy-2-methoxyphenyl boronic acid andisopropylamine. The solvent was removed and then water and EtOAc wereadded. The phases were separated and the aqueous one was extracted twicewith EtOAc. The organic extracts were combined and dried (Na₂SO₄), andconcentrated. The residue was triturated in acetonitrile to give thetitle compound. t_(R): 0.63 min (LC-MS 2); ESI-MS: 238.5 [M+H]⁺ (LC-MS2).

Example 2215-(5-Chloro-2-methyl-phenyl)-6-(4-chloro-2-methyl-phenyl)-2-(2-ethyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate F and 2-ethylphenylboronic acid.The reaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were combined, dried (Na₂SO₄) andconcentrated. The product was purified by flash chromatography(hexane/EtOAc, 95:5→1:1). The residue was purified by SFC (Column: NH2Reprosil 70, 30×250 mm. Flow 100 mL/min. scCO2/MeOH, gradient of MeOH15-20% in 6 min). to give the title compound. t_(R): 1.42/1.47 min(LC-MS 2); ESI-MS: 518.2/520.2 [M+H]⁺ (LC-MS 2).

Example 2223-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was obtained after preparative chiral chromatographyseparation of the racemic example 9. (Column: Chiralcel OD, 30×250 mm,heptane/EtOH, 65:35). t_(R): 1.17/1.21 min (LC-MS 2); ESI-MS:591.3/593.3 [M+H]⁺ (LC-MS 2).

Example 2233-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-N,N-dimethyl-benzamide

The title compound was obtained after preparative chiral chromatographyseparation of the racemic example 9. (Column: Chiralcel OD, 30×250 mm,heptane/EtOH, 65:35). t_(R): 1.17/1.21 min (LC-MS 2); ESI-MS:591.3/593.3 [M+H]⁺ (LC-MS 2).

Example 2246-(4-Chloro-2-methyl-phenyl)-5-(4-chloro-pyridin-2-yl)-2-(5-hydroxymethyl-2-methoxy-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate I and product from step 224.1. Thereaction mixture was diluted in EtOAc/water and extracted twice withEtOAc. The combined organic extracts were combined, dried (Na₂SO₄) andconcentrated. The residue was purified by preparative chromatography(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 50-90% in 16 min). The residue was purified by SFC(Column: 2-EP, 30×250 mm. Flow 100 mL/min. scCO2/MeOH, gradient of MeOH:20 to 25% in 6 min). to give the title compound. t_(R): 1.25 min (LC-MS2); ESI-MS: 537.2/539.2 [M+H]⁺ (LC-MS 2).

Step 224.1 (4-(isopropylcarbamoyl)-2-methoxyphenyl)boronic acid

The title compound was prepared in analogy to the procedure describedfor example 18 from 5-formyl-2-methoxy-phenylboronic acid. The reactionmixture was poured in Ice-water and was extracted twice with EtOAc. Theorganic extracts were combined, dried (Na2SO4) and concentrated to givethe title compound. t_(R): 0.49 min (LC-MS2); ESI-MS: 364.6 [M+H]⁺(LC-MS 2).

Example 2253-[(R)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide

The title compound was obtained after preparative chiral SFC separationof the racemic example 12. (Column: Chiralcel OD-H, 30×250 mm. Flow 80mL/min. scCO2/EtOH/2-propylamine, 75:25:0.25). t_(R): 8.06 min (Column:Chiralpak IA, 4.6×250 mm. Flow 3 mL/min. scCO2/EtOH/2-propylamine,80:20:0.2). ESI-MS: 605.3.3/607.2 [M+H]⁺ (LC-MS 2).

Example 2263-[(S)-6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-N-isopropyl-4-methoxy-benzamide

The title compound was obtained after preparative chiral SFC separationof the racemic example 12. (Column: Chiralcel OD-H, 30×250 mm. Flow 80mL/min. scCO2/EtOH/2-propylamine, 75:25:0.25). t_(R): 4.67 min (Column:Chiralpak IA, 4.6×250 mm. Flow 3 mL/min. scCO2/EtOH/2-propylamine,80:20:0.2). ESI-MS: 605.3.3/607.2 [M+H]⁺ (LC-MS 2).

Example 2276-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 227.1 (100 mg, 0.18 mmol) andHATU (106 mg, 0.28 mmol) in DMF (1.5 mL) was added DIPEA (66 μL, 0.38mmol) and the mixture was stirred under microwave irradiation at 105° C.for 30 min. The crude was purified by preparative HPLC (Waters Sun FireC18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile5-100% in 20 min) to give the title compound. t_(R): 1.25 min (LC-MS 2);ESI-MS: 521.2/523.2 [M+H]⁺ (LC-MS 2).

Step 227.15-[(4-Chloro-2-methyl-phenyl)-(5-chloro-2-methyl-pyridin-3-ylamino)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid

To a solution of the product from step 227.2 (220 mg, 0.39 mmol) indioxane/H₂O (3.7 mL, 4:1) was added LiOH.H₂O (25 mg, 0.60 mmol) and themixture was stirred at 60° C. for 4 h. The reaction mixture was pouredinto a 10% citric acid solution and stirred for 10 min. The mixture wasextracted with EtOAc. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The product was purified by flash chromatography(heptane/EtOAc). t_(R): 1.16 min (LC-MS2); ESI-MS: 539.2/541.2 [M+H]⁺(LC-MS 2).

Step 227.25-[(4-Chloro-2-methyl-phenyl)-(5-chloro-2-methyl-pyridin-3-ylamino)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

To a solution of the product from step 227.6 (300 mg, 0.576 mmol) inCH₂Cl₂ (5 ml) was added the product from step 227.3 (200 mg, 1.403 mmol)and the mixture was stirred at 40° C. for 20 h. The reaction mixture wasdiluted in EtOAc and extracted with citric acid (10%). The organic phasewas washed with brine, dried (Na2SO4), filtered and concentrated. Theproduct was purified by flash chromatography (heptane/EtOAc). t_(R):1.40 min (LC-MS 2); ESI-MS: 567.2/569.2 [M+H]⁺ (LC-MS 2).

Step 227.3 5-Chloro-2-methyl-pyridin-3-ylamine

The title compound was prepared in analogy to the procedure describedfor example 100.4 using the product from step 227.4. The reaction wasperformed in EtOH at rt, for 20 h. After extraction, the product wasused without purification. t_(R): 0.42 min (LC-MS2); ESI-MS: 143.0/145.0[M+H]⁺ (LC-MS 2).

Step 227.4 5-Chloro-2-methyl-3-nitro-pyridine

To a suspension of the product from step 227.5 (9.9 g, 23.4 mmol) in H₂O(25 mL) was added concentrated HCl (25 mL, 304 mmol) and the mixture wasstirred at 100° C. for 20 h. The reaction mixture was allowed to cool toRT and extracted with Et₂O. The organic layer was washed with brine,dried (Na₂SO₄), filtered and concentrated. The product was used withoutfurther purification for the next step. t_(R): 0.80 min (LC-MS 2).

Step 227.5 2-(5-Chloro-3-nitro-pyridin-2-yl)-malonic acid diethyl ester

To a solution of NaH (2 g, 50 mmol) in DMF (30 mL) was addeddiethylmalonate (7.9 mL, 52 mmol) and the mixture was stirred at rt for10 min. A solution of 2,5-dichloro-3-nitropyridine (5 g, 25.9 mmol) inDMF (10 mL) was added and the mixture was stirred at 40° C. for 2 h. Thereaction mixture was concentrated. The residue was dissolved in H₂O andpH was adjusted to 7 with 2M HCl. The aqueous solution was extractedwith Et₂O. The organic layer was washed with H₂O, dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (heptane/EtOAc). t_(R): 1.07 min (LC-MS 2); ESI-MS:317.2/319.1 [M+H]⁺ (LC-MS 2).

Step 227.65-[(4-Chloro-2-methyl-phenyl)-methanesulfonyloxy-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

To a solution of intermediate D (3.3 g, 7.6 mmol) and Et₃N (2.6 mL, 18.7mmol) in CH₂Cl₂ at 0° C. was added MsCl (1.2 mL, 15.4 mmol) and themixture was stirred at rt for 1 h. The reaction mixture was poured intocold water and extracted with CH₂C₂. The organic layer was dried(Na₂SO₄), filtered and concentrated. The product was used withoutfurther purification. t_(R): 1.44 min (LC-MS 2); ESI-MS: 457 (reactionwith MeOH) [M+H]⁺ (LC-MS 2).

Example 228N-{3-[6-(4-Chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzyl}-2-hydroxy-acetamide

The product from step 228.1 (106 mg, 0.16 mmol) was dissolved in MeOH(2.7 mL) with K2CO3 (56 mg, 0.41 mmol). The reaction mixture was stirredat RT for 3 h. It was diluted in EtOAc/water and extracted twice withEtOAc. The organic extracts were combined, dried (Na₂SO₄) andconcentrated. The residue was triturated in EtOAc to give the titlecompound. t_(R): 1.15 min (LC-MS 2); ESI-MS: 607.3/609.2 [M+H]⁺ (LC-MS2).

Step 228.1 Acetic acid{3-[6-(4-chloro-2-methyl-phenyl)-5-(5-chloro-2-methyl-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzylcarbamoyl}-methylester

The product from example 16 (90 mg, 0.16 mmol) was dissolved in THF (1.6mL) with TEA (27 μL, 0.20 mmol) and then acetoxyacetyl chloride (19 μL,0.18 mmol) was added. The reaction mixture was stirred at RT for 30 min.It was then concentrated to give the title compound. t_(R): 1.24 min(LC-MS 2); ESI-MS: 649.3/651.2 [M+H]⁺ (LC-MS 2).

Example 2295-[5-Chloro-1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 227 using the product from step 229.1. The reaction wasperformed at 110° C. for 45 min. t_(R): 1.04 min (LC-MS 2); ESI-MS:567.2/569.2 [M+H]⁺ (LC-MS 2).

Step 229.15-[[5-Chloro-1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 227.1 using the product from step 229.2. t_(R): 0.93 min (LC-MS2); ESI-MS: 585.2/587.2 [M+H]⁺ (LC-MS 2).

Step 229.25-[[5-Chloro-1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 227.2 using the products from steps 227.6 and 229.3. t_(R):1.18 min (LC-MS 2); ESI-MS: 613.2/615.2 [M+H]⁺ (LC-MS 2).

Step 229.3 5-Amino-3-chloro-1-(2-hydroxy-ethyl)-1H-pyridin-2-one

A mixture of the compound prepared in step 229.4 (3.4 g, 18.1 mmol),iron powder (3 g, 54.3 mmol), EtOH (68 mL), and a saturated aqueoussolution of NH₄Cl (17 mL) was stirred for 1 h at reflux. The reactionmixture was allowed to cool to rt, filtered through a pad of celite, andconcentrated. The residue was purified by flash chromatography(CH₂Cl₂/MeOH, 99:1) to provide the title compound. ESI-MS: 189 [M+H]⁺(LC-MS 2); R_(f)=0.17 (CH₂Cl₂/MeOH, 99:1).

Step 229.4 3-Chloro-1-(2-hydroxy-ethyl)-5-nitro-1H-pyridin-2-one

-   2-Bromo-ethanol (17.2 g, 138 mmol) was added dropwise to a cold (0°    C.) mixture of the compound prepared in step 229.5 (12 g, 69 mmol)    and K₂CO₃ (19 g, 138 mmol) in DMF (60 mL). The reaction mixture was    allowed to warm to rt, stirred for 48 h, cooled to 0° C., quenched    by slow addition of ice cooled water, and stirred for 2 h. The    resulting precipitate was collected by vacuum filtration to afford    11 g of the title compound. ESI-MS: 217 [M−H]⁻ (LC-MS 2); R_(f)=0.27    (CH₂Cl₂/MeOH, 95:5).

Step 229.5 3-Chloro-5-nitro-pyridin-2-ol

To a warm (50° C.) solution of 2-hydroxy-5-nitro-pyridine (17 g, 121mmol) in concentrated HCl (80 mL) was added dropwise NaClO₃ (4.5 g, 42.5mmol) in water (70 mL), keeping the internal temperature below 60° C.The reaction mixture was stirred for 15 min and then cooled to 0° C. Theresulting precipitate was collected by vacuum filtration and dried toprovide 19.7 g of the title compound. ESI-MS: 173 [M−H]⁻ (LC-MS 2);R_(f)=0.55 (hexane/EtOAc, 1:1).

Example 2305-[5-Chloro-1-(2-methoxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 227 using the product from step 230.1. The crude waspurified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) to givethe title compound. t_(R): 1.14 min (LC-MS 2); ESI-MS: 581.2/583.2[M+H]⁺ (LC-MS 2).

Step 230.15-[[5-Chloro-1-(2-methoxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 227.1 using the product from step 230.2. The reaction mixturewas dissolved in CH₂Cl₂ and dimethylamine hydrochloride (1 eq) and adrop of MeOH were added. The mixture was stirred at rt 1 h, thenconcentrated. The residue was suspended in CH₂Cl₂ and filtered. Themother liquor was concentrated. The crude was purified by preparativeHPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min) to give the title compound.t_(R): 1.00 min (LC-MS 2); ESI-MS: 599.3/601.2 [M+H]⁺ (LC-MS 2).

Step 230.25-[[5-Chloro-1-(2-methoxy-ethyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 227.2 using the products from steps 227.6 and 230.3. Theproduct was purified by flash chromatography (heptane/EtOAc, 1:1→0:100).t_(R): 1.28 min (LC-MS 2); ESI-MS: 627.3/629.2 [M+H]⁺ (LC-MS 2).

Step 230.3 5-Amino-3-chloro-1-(2-methoxy-ethyl)-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure described instep 229.4 but using the compound prepared in step 230.4. The crudematerial was purified by flash chromatography (CH₂Cl₂/MeOH, 95:5) toprovide the title compound. ESI-MS: 203 [M+H]⁺ (LC-MS 2); R_(f)=0.28(CH₂Cl₂/MeOH, 99.75:0.25).

Step 230.4 3-Chloro-1-(2-methoxy-ethyl)-5-nitro-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure described instep 229.5 but using 1-bromo-2-methoxy-ethane. The reaction mixture wasallowed to warm to rt, stirred for 4 h, heated to 70° C., stirred for 4h, and quenched by addition of ice cooled water. The resultingprecipitate was collected by vacuum filtration to afford the titlecompound. ESI-MS: 233 [M−H]⁻ (LC-MS 2); R_(f)=0.33 (CH₂Cl₂/MeOH, 95:5).

Example 2315-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 227 using the product from step 231.1. The reaction wasperformed at 110° C. for 45 min. The crude was purified by preparativeHPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min) to give the title compound.t_(R): 1.10 min (LC-MS 2); ESI-MS: 537.2/539.1 [M+H]⁺ (LC-MS 2).

Step 231.15-[(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 230.1 using the product from step 231.2. t_(R): 0.97 min (LC-MS2); ESI-MS: 555.2/557.2 [M+H]⁺ (LC-MS 2).

Step 231.25-[(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 227.2 using the products from steps 227.6 and J3. The productwas purified by flash chromatography (heptane/EtOAc, 1:1→0:100). t_(R):1.26 min (LC-MS 2); ESI-MS: 583.2/585.2 [M+H]⁺ (LC-MS 2).

Example 2325-(5-Chloro-1-ethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 227 using the product from step 232.1. The reaction wasperformed under microwave irradiation at 100° C. for 5.5 h and at 110°C. for 4 h. The reaction mixture was poured into a 10% citric acidsolution and stirred for 10 min. The mixture was extracted with CH₂Cl₂.The organic layer was dried (Na₂SO₄), filtered and concentrated. Thecrude was purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm,5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20min) to give the title compound. t_(R): 1.12 min (LC-MS 2); ESI-MS:551.2/553.2 [M+H]⁺ (LC-MS 2).

Step 232.15-[(5-Chloro-1-ethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid anion

The title compound was prepared in analogy to the procedure describedfor step 227.1 using the product from step 232.2. After completion, thereaction mixture was concentrated. The resulting lithium salt was usedwithout further purification. t_(R): 1.04 min (LC-MS 2); ESI-MS:569.2/571.2 [M+H]⁺ (LC-MS 2).

Step 232.25-[(5-Chloro-1-ethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-2-(2-methoxy-phenyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 227.2 using the products from steps 227.6 and 232.3. Theproduct was purified by flash chromatography (heptane/EtOAc, 7:3→0:100).t_(R): 1.30 min (LC-MS 2); ESI-MS: 597.3/599.3 [M+H]⁺ (LC-MS 2).

Step 232.3 5-Amino-3-chloro-1-ethyl-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure described instep 229.4 but using the compound prepared in step 232.4. The crudematerial was purified by flash chromatography (CH₂Cl₂/MeOH, 95:5) toprovide the title compound. t_(R): 2.39 min (HPLC 3); R_(f)=0.14(CH₂Cl₂/MeOH, 9:1).

Step 232.4 3-Chloro-1-ethyl-5-nitro-1H-pyridin-2-one

The title compound was prepared in analogy to the procedure described instep 229.5 but using ethyl iodide. The crude material was purified byflash chromatography (hexane/EtOAc, 92:8) to afford the title compound.t_(R): 3.49 min (HPLC 2); ESI-MS: 203 [M+H]⁺ (LC-MS 2); R_(f)=0.49(hexane/EtOAc, 1:1).

Example 2332-(2-Amino-pyridin-4-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using intermediate G and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine. Afterworkup, the residue was triturated in Et₂O and hexane to give the titlecompound. t_(R): 0.96 min (LC-MS 2); ESI-MS: 496.2/498.2 [M+H]⁺ (LC-MS2).

Example 2345-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-[5-(1-hydroxy-2-methyl-propyl)-2-methoxy-phenyl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

To a solution of the product from step 234.1 (90 mg, 0.17 mmol) in THF(3 mL) at 0° C. was added isopropylmagnesium bromide 1M (1.1 mL, 1.1mmol) and the mixture was stirred at 0° C. for 1.5 h. The reactionmixture was quenched with H₂O and extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The crude was purified by flash chromatography (heptane/EtOAc,100:0→20:80) to afford the title compound. t_(R): 1.26 min (LC-MS 2);ESI-MS: 582.3/584.3 [M+H]⁺ (LC-MS 2).

Step 234.13-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-4-methoxy-benzaldehyde

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate G and 5-formyl-2-methoxyphenylboronicacid. The crude was purified by flash chromatography (CH₂Cl₂/MeOH,100:0→90:10) then was purified by MPLC (Column: xBridge C18, 30×100 mm,Flow: 30 mL/min. 5-60% B in 4 min; A=0.1% TFA in water, B=0.1% TFA inCH₃CN) to afford the title compound. t_(R): 1.17 min (LC-MS 2); ESI-MS:538.3/540.3 [M+H]⁺ (LC-MS 2).

Example 2355-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-2-[5-(1-hydroxy-ethyl)-2-methoxy-phenyl]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 234 using methylmagnesium bromide. After extraction, theresidue was purified by MPLC (Column: xBridge C18, 30×100 mm, Flow: 30mL/min. 5-60% B in 4 min to 100% B in 3 min; A=0.1% TFA in water, B=0.1%TFA in CH₃CN) to afford the title compound. t_(R): 1.16 min (LC-MS 2);ESI-MS: 554.3/556.3 [M+H]⁺ (LC-MS 2).

Example 2365-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(4-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate G and 2-methoxy-5-pyridineboronic acid.The product was purified by preparative HPLC (Waters Sun Fire C18,30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradient acetonitrile40-80% in 16 min) to give the title compound. t_(R): 1.20 min (LC-MS 2);ESI-MS: 511.3 [M+H]⁺ (LC-MS 2).

Example 2375-(5-(3-chloro-2-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-methoxy-N,N-dimethylpyridazine-3-carboxamide

The title compound was prepared in analogy to the procedure describedfor example 1 using intermediate G and the product from step 237.1. Thereaction was performed at 90° C. After extraction, the product waspurified by preparative MPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 40-80% in 16 min) to givethe title compound. t_(R): 1.10 min (LC-MS 2); ESI-MS: 583.1/585.1[M+H]⁺ (LC-MS 2).

Step 237.1 (6-(dimethylcarbamoyl)-3-methoxypyridazin-4-yl)zinc

The title compound was prepared in analogy to the procedure describedfor step 96.2 using the product from step 237.2.

Step 237.2 6-methoxy-N,N-dimethylpyridazine-3-carboxamide

To a solution of 6-methoxypyridazine-3-carboxylic acid (1.56 g, 10.12mmol) in THF (21 mL) at 5° C. was added1-chloro-N,N,2-trimethyl-1-propenylamine (1.87 mL, 14.17 mmol) and themixture was stirred at rt for 1 h. dimethyl amine 2M in THF (20.2 mL,40.5 mmol) was added and the mixture was stirred at rt for 2 h. Thereaction mixture was diluted with EtOAc and extracted with H₂O. Theorganic layers were dried (Na₂SO₄), filtered and concentrated to affordthe title compound. t_(R): 0.46 min (LC-MS 2); ESI-MS: 182.1 [M+H]⁺(LC-MS 2).

Example 2382-(4-(5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-2-methylphenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-5-methoxypyridin-2-yl)acetonitrile

The title compound was obtained in analogy to the procedure describedfor example 29 but using the products from steps 238.1 and 238.4. Thereaction mixture was diluted in EtOAc and extracted with a saturatedNaHCO₃ solution. The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. The product was purified by flashchromatography (CH₂Cl₂/MeOH, 100:0→40:60). t_(R): 1.00 min (LC-MS 2);ESI-MS: 577.1/579.1 [M+H]⁺ (LC-MS 2).

Step 238.12-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-2-methylphenyl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

The title compound was obtained in analogy to the procedure describedfor step 91.1 but using the product from step 238.2. The reactionmixture was extracted with a saturated NaHCO₃ solution. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and concentrated.The product was used without further purification. t_(R): 1.06 min(LC-MS 2); ESI-MS: 509.0/511.0/513.0 [M+H]⁺ (LC-MS 2).

Step 238.22-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was obtained in analogy to the procedure describedfor step 227.1 but using the product from step 238.3. The reaction wasperformed at rt. t_(R): 1.06 min (LC-MS 2); ESI-MS: 527.0/529.0 [M+H]⁺(LC-MS 2).

Step 238.32-Bromo-5-[(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor step E2 but using the product from step 100.4 and intermediate C.The reaction mixture was extracted with H₂O. The organic layers werewashed with a saturated NaHCO₃ solution, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography(heptane/EtOAc, 1:1→0:100). t_(R): 1.26 min (LC-MS 2); ESI-MS:555.0/557/0.559.0 [M+H]⁺ (LC-MS 2).

Step 238.42-(5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetonitrile

The title compound was obtained in analogy to the procedure describedfor intermediate S using 2-(4-chloro-5-methoxypyridin-2-yl)acetonitrile.The reaction was performed at 90° C. The reaction mixture was dilutedwith toluene and filtered over Hyflo to afford the title compound.

Example 2394-(5-(3-chloro-2-fluorophenyl)-2-(2-(cyanomethyl)-5-methoxypyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-4-yl)-3-methylbenzonitrile

The title compound was obtained in analogy to the procedure describedfor step 97.1 but using the products from steps 239.1 and 238.4. Theresidue was purified by flash chromatography (heptane/CH₂Cl₂/MeOH,90:9.5:0.5→15:81:4). The residue was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min). The residue was purified byflash chromatography (CH₂Cl₂/MeOH, 100:0→90:10) to give the titlecompound. t_(R): 1.01 min (LC-MS 2); ESI-MS: 555.2/557.1 [M+H]⁺ (LC-MS2).

Step 239.14-(2-bromo-5-(3-chloro-2-fluorophenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-4-yl)-3-methylbenzonitrile

The title compound was obtained in analogy to the procedure describedfor step 93.2 but using the product from step 239.2. After completion,the reaction mixture was extracted with a saturated NaHCO₃ solution. Theorganic layers were washed with water then brine, dried (Na₂SO₄),filtered and concentrated. The residue was triturated in hexane toafford the title compound. t_(R): 1.06 min (LC-MS 2); ESI-MS:487.0/489.0 [M+H]⁺ (LC-MS 2).

Step 239.22-bromo-5-((3-chloro-2-fluorophenylamino)(4-cyano-2-methylphenyl)methyl)-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was obtained in analogy to the procedure describedfor step 93.2 but using the product from step 239.3. t_(R): 1.13 min(LC-MS 2); ESI-MS: 505.0/507.0 [M+H]⁺ (LC-MS 2).

Step 239.3 ethyl2-bromo-5-((3-chloro-2-fluorophenylamino)(4-cyano-2-methylphenyl)methyl)-1-isopropyl-1H-imidazole-4-carboxylate

The title compound was obtained in analogy to the procedure describedfor step E2 but using the product from step 182.4 and3-chloro-2-fluoroaniline. After extraction, the residue was purified byflash chromatography (heptane/EtOAc, 90:10→0:100). t_(R): 1.30 min(LC-MS 2); ESI-MS: 533.0/535.1 [M+H]⁺ (LC-MS 2).

Example 2404-(5-(3-chloro-4-fluorophenyl)-2-(2-(cyanomethyl)-5-methoxypyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-4-yl)benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 97.1 but using the product from steps 238.4 and intermediateAC. The residue was purified by flash chromatography(heptane/CH₂Cl₂/MeOH, 90:9.5:0.5→15:81:4). The residue was purified bypreparative HPLC (Waters Sunfire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min). t_(R):1.00 min (LC-MS 2); ESI-MS: 541.1/543.2 [M+H]⁺ (LC-MS 2)

Example 241{4-[5-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was obtained in analogy to the procedure describedfor step 97.1 but using the products from steps 241.1 and 238.4. Thereaction was performed at 80° C. After extraction, the residue waspurified by flash chromatography (heptane/CH₂Cl₂/MeOH,90:9.5:0.5→15:81:4). The residue was purified by preparative HPLC(Waters Sunfire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 5-100% in 20 min). t_(R): 1.14 min (LC-MS 2);ESI-MS: 550.2/552.1 [M+H]⁺ (LC-MS 2); R_(f)=0.21 (CH₂Cl₂/MeOH, 20:1).

Step 241.12-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained in analogy to the procedure describedfor example AK but using the product from step 241.2. The residue waspurified by flash chromatography (heptane/EtOAc, 2:1). t_(R): 1.21 min(LC-MS 2); ESI-MS: 482.1/484.1/486.1 [M+H]⁺ (LC-MS 2)

Step 241.22-Bromo-N-(3-chloro-4-fluorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-isopropyl-1H-imidazole-4-carboxamide

The title compound was obtained in analogy to the procedure describedfor step AK1 but using intermediate B and 3-chloro-4-fluoroaniline.After completion, the reaction mixture was diluted in EtOAc andextracted with a 1M citric acid solution. The organic layers were washedwith a saturated NaHCO₃ and brine, dried (Na₂SO₄), filtered andconcentrated. The residue was purified by flash chromatography (CH₂Cl₂).t_(R): 1.43 min (LC-MS 2); ESI-MS: 500.0 [M+H]⁺ (LC-MS 2)

Example 2424-[5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-3-methyl-benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 97.1 but using the products from steps 186.1 and 238.4. Thereaction was performed at 80° C. After extraction, the residue waspurified by flash chromatography (CH₂Cl₂/MeOH, 100:0→97:3). The residuewas triturated in CH₂Cl₂/TBME to afford the title compound. t_(R): 1.05min (LC-MS 2); ESI-MS: 551.2/553.1 [M+H]⁺ (LC-MS 2).

Example 2436-(4-Chloro-phenyl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the products from steps 262.1 and 105.1. Afterextraction, the product was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 20-40% in 16 min). The residue was then purified by SFCchromatography (Column DEAP, 250×30 mm, 5 μm, flow 100 mL/min, grad10-15% over 6 min) to give the title compound. t_(R): 0.89 min (LC-MS2); ESI-MS: 519.2/521.2 [M+H]⁺ (LC-MS 2).

Example 2445-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(3-methoxy-1-methyl-6-oxo-1,6-dihydro-pyridazin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained in analogy to the procedure describedfor example 1 but using intermediate G and the product from step 244.1.The reaction was performed at 90° C. for 1.5 h. After a purification bypreparative HPLC, the residue was purified by SFC chromatography(Column: Reprosil 70 NH₂, 250×30 mm, 5 μm, flow 100 mL/min, grad 5-50%)to afford the title compound. t_(R): 1.14 min (LC-MS 2); ESI-MS:542.1/544.1 [M+H]⁺ (LC-MS 2).

Step 244.1 (3-methoxy-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)zinc

The title compound was prepared in analogy to the procedure describedfor step 96.2 using the product from step 244.2.

Step 244.2 6-Methoxy-2-methyl-2H-pyridazin-3-one

The title compound was obtained in analogy to the procedure describedfor step 105.2 but using 3-chloro-6-methoxypyridazine. The reaction wasperformed at 50° C. for 2 h. 1M NaOH solution was added and the mixturewas stirred at rt for 20 h. The reaction mixture was diluted with CH₂Cl₂and extracted with H₂O. The organic layer was dried (Na₂SO₄), filteredand concentrated to give the title compound. t_(R): 0.48 min (LC-MS 2);ESI-MS: 141.1 [M+H]⁺ (LC-MS 2).

Example 2455-(5-Chloro-2-methyl-phenyl)-6-(5-chloro-pyridin-2-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 29 but using the product from step 245.1 and intermediate W.After extraction, the crude was purified by preparative HPLC. Theresidue was triturated in diisopropyl ether to afford the titlecompound. t_(R): 1.19 min (LC-MS 2); ESI-MS: 552.3 [M+H]⁺ (LC-MS 2).

Step 245.12-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(5-chloro-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazo-4-one

To a solution of the product from step 245.2 (440 mg, 638 mmol) in EtOH(15 mL) was added Mo(CO)₆ (253 mg, 958 mmol) and the mixture was stirredat 80° C. for 5 h. The mixture was concentrated then purified by flashchromatography (heptane/EtOAc, 100:0→0:100) to afford the titlecompound. t_(R): 1.13 min (LC-MS 2); ESI-MS: 479.0/481.1/483.1 [M+H]⁺(LC-MS 2).

Step 245.22-Bromo-5-(5-chloro-2-methyl-phenyl)-6-(5-chloro-1-oxy-pyridin-2-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 245.3. After completion,the reaction mixture was quenched with MeOH and concentrated. Theresidue was purified by flash chromatography (heptane/EtOAc,100:0→0:100) to afford the title compound. t_(R): 0.96 min (LC-MS 2);ESI-MS: 494.9/497.0/499.0 [M+H]⁺ (LC-MS 2).

Step 245.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(5-chloro-1-oxy-pyridin-2-yl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 245.4. After pH was adjustedat 5, the mixture was concentrated and the resulting suspension wasfiltered. The resulting solid was dried to afford the title compound.t_(R): 1.04 min (LC-MS 2); ESI-MS: 513.0/515.0/517.2 [M+H]⁺ (LC-MS 2).

Step 245.42-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(5-chloro-1-oxy-pyridin-2-yl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 245.5 and5-chloro-2-methylaniline. The reaction mixture was extracted with asaturated aqueous NaHCO₃ solution. The organic layer was dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (heptane/EtOAc, 100:0→0:100) to provide the titlecompound. t_(R): 1.24 min (LC-MS 2); ESI-MS: 541.0/543.1/545.0 [M+H]⁺(LC-MS 2).

Step 245.52-Bromo-5-[(5-chloro-1-oxy-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

To a solution of the product from step 245.6 (12.7 g, 31.5 mmol) inCHCl₃ at 0° C. was added m-CPBA (17.7 g, 103 mmol) and the mixture wasstirred at rt for 5 h. The reaction mixture was diluted with CH₂Cl₂ andextraction with a saturated Na₂CO₃ solution. The organic layer was dried(Na₂SO₄), filtered and concentrated. The product was used withoutfurther purification for the next step. t_(R): 0.78 min (LC-MS 2);ESI-MS: 418.0/420.0 [M+H]⁺ (LC-MS 2).

Step 245.62-Bromo-5-[(5-chloro-pyridin-2-yl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate B but using 5-chloro-2-formylpyridine. Aftercompletion, the reaction mixture was diluted with EtOAc and extractedwith a saturated NaHCO₃ solution. The organic layer was dried (Na₂SO₄),filtered and concentrated. The residue was purified by flaschromatography (heptane/EtOAc, 100:0→0:100) to give the title compound.t_(R): 1.00 min (LC-MS 2); ESI-MS: 402.0/404.0 [M+H]⁺ (LC-MS 2).

Example 2464-[5-(3-Chloro-2-fluoro-phenyl)-3-isopropyl-2-(4-methoxy-2-methylamino-pyrimidin-5-yl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 91.1 but using the product from step 246.1 and intermediate Z.The reaction was performed at 100° C. The residue was purified bypreparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 15-65% in 20 min) and thenby preparative TLC (EtOAc/MeOH, 85:15) to afford the title compound.t_(R): 1.03 (LC-MS 2); ESI-MS: 550.1/552.1 [M+H]⁺ (LC-MS 2); R_(f)=0.32(EtOAc/MeOH, 85:15).

Step 246.14-[2-Bromo-5-(3-chloro-2-fluoro-phenyl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 93.1 but using the product from step 246.2. After extraction,the residue was triturated in MeOH and filtered to afford the titlecompound. The rest of the mother liquor was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 30-80% in 20 minto afford the title compound.t_(R): 1.07 (LC-MS 2); ESI-MS: 491.1/493.1 [M+H]⁺ (LC-MS 2).

Step 246.22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was obtained in analogy to the procedure describedfor step E1 but using the product from step 246.3. t_(R): 1.13 min(LC-MS 2); ESI-MS: 509.3/511.1/513.2 [M+H]⁺ (LC-MS 2).

Step 246.32-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-3-fluoro-phenyl)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 167.4 and3-chloro-2-fluoroaniline. The mixture was extracted with a saturatedaqueous NaHCO₃ solution. The organic layers were dried (Na₂SO₄),filtered and concentrated. The product was purified by flashchromatography (hexane/EtOAc, 100:0→0:100). t_(R): 1.31 min (LC-MS 2);ESI-MS: 537.2/539.2/541.2 [M+H]⁺ (LC-MS 2).

Example 2474-[5-(3-Chloro-2-fluoro-phenyl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 91.1 but using the product from step 246.1 and intermediate W.The reaction was performed at 100° C. After extraction, the residue waspurified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1%TFA-water/acetonitrile; gradient acetonitrile 38-60% in 20 min) and thentriturated in diisopropylether to afford the title compound. t_(R): 1.13(LC-MS 2); ESI-MS: 564.1 [M+H]⁺ (LC-MS 2).

Example 2484-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro-benzonitrile

The title compound was obtained in analogy to the procedure describedfor step 91.1 but using the product from step 246.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. The reaction was performed at100° C. After extraction, the residue was purified by preparative HPLC(Waters Sun Fire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile;gradient acetonitrile 40-65% in 20 min) and then purified by preparativeTLC (EtOAc/EtOH, 85:15) to afford the title compound. t_(R): 1.06 (LC-MS2); ESI-MS: 551.1/553.1 [M+H]⁺ (LC-MS 2); R_(f)=0.41 (EtOAc/EtOH,85:15).

Example 2494-[5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyrimidine-2-carboxylicacid dimethylamide

The title compound was obtained in analogy to the procedure describedfor step 96.1 but using intermediate G and the product from step and theproduct from step 249.1. The reaction was performed at 90° C. Afterextraction, the residue was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 40-60% in 16 min) to afford the title compound. t_(R): 1.06(LC-MS 2); ESI-MS: 583.1/585.1 [M+H]⁺ (LC-MS 2).

Step 249.1 (2-(dimethylcarbamoyl)-5-methoxypyrimidin-4-yl)zinc

The title compound was obtained in analogy to the procedure describedfor step 96.2 but using the product from step 249.2. The reaction wasstirred at rt for 16 h.

Step 249.2 5-Methoxy-pyrimidine-2-carboxylic acid dimethylamide

The title compound was obtained in analogy to the procedure describedfor step 237.2 but using 5-methoxy-2-pyrimidine carboxylic acid. Aftercompletion, the reaction mixture was diluted with EtOAc and extractedwith H₂O, NaCl was added to the aqueous layer and extracted with EtOAc.The organic layers were dried (Na₂SO₄), filtered and concentrated toafford the title compound. t_(R): 0.44 min (LC-MS 2); ESI-MS: 182.1[M+H]⁺ (LC-MS 2).

Example 250{4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was obtained after preparative chiral SFC separation(Column: Chiralpak AD-H, 30×250 mm, Flow 140 g/min, CO₂/EtOH 75:25,Detection: UV 210 nm, cycle time 12 min) of the racemic product ofexample 136. t_(R): 4.25 min (Column: Chiralpak AD-H, 4.6×250 mm, Flow 3mL/min. CO₂/EtOH 7:3, Detection: UV 210 nm). t_(R): 1.12 min (LC-MS 2);ESI-MS: 550.1/552.1 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-de, 400 MHz)

8.57 (s, 1H), 7.

7H), 6.58 (s, 1H), 4.22 (s, 2H), 4.14-4.06 (m, 1H), 3.93 (s, 3H), 1.34(d, 3H), 0.50 (d, 3H).

Example 251{4-[(R)-5-(3-Chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-2-yl]-5-methoxy-pyridin-2-yl}-acetonitrile

The title compound was obtained after preparative chiral SFC separation(Column: Chiralpak AD-H, 30×250 mm, Flow 140 g/min, CO₂/EtOH 75:25,Detection: UV 210 nm, cycle time 12 min) of the racemic product ofexample 136. t_(R): 5.27 min (Column: Chiralpak AD-H, 4.6×250 mm, Flow 3mL/min. CO₂/EtOH 7:3, Detection: UV 210 nm). t_(R): 1.12 min (LC-MS 2);ESI-MS: 550.1/552.1 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400 MHz)

8.57 (s, 1H), 7. 7H), 6.58 (s, 1H), 4.22 (s, 2H), 4.14-4.06 (m, 1H),3.93 (s, 3H), 1.34 (d, 3H), 0.50 (d, 3H).

Example 2524-[(S)-5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separation(Column: IA 20 μm, 30×500 mm, Flow 60 mL/min, heptane/EtOH/MeOH66:17:17, Detection: UV 210 nm) of the racemic product of example 135.t_(R): 13.01 min (Column: Chiralpak AS-H, 4.6×250 mm, Flow 1 mL/min.heptane/EtOH/MeOH 70:15:15, Detection: UV 220 nm). t_(R): 1.01 min(LC-MS 2). ESI-MS: 537.2/538.2 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400MHz) δ ppm 8.58 (s, 1H), 7.88-7.76 (m, 3H), 7.57-7.49 (m, 3H), 7.21-7.12(m, 2H), 6.74 (s, 1H), 4.22 (s, 2H), 4.14-4.06 (m, 1H), 3.94 (s, 3H),1.93 (s, 3H), 1.33 (d, 3H), 0.55-0.43 (m, 3H).

Example 2534-[(R)-5-(5-Chloro-2-methyl-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separation(Column: IA 20 μm, 30×500 mm, Flow 60 mL/min, heptane/EtOH/MeOH66:17:17, Detection: UV 210 nm) of the racemic product of example 135.t_(R): 25.19 min (Column: Chiralpak AS-H, 4.6×250 mm, Flow 1 mL/min.heptane/EtOH/MeOH 70:15:15, Detection: UV 220 nm). t_(R): 1.01 min(LC-MS 2). ESI-MS: 537.2/538.2 [M+H]⁺ (LC-MS 2); ¹H-NMR (DMSO-d₆, 400MHz) δ ppm 8.58 (s, 1H), 7.88-7.76 (m, 3H), 7.57-7.49 (m, 3H), 7.21-7.12(m, 2H), 6.74 (s, 1H), 4.22 (s, 2H), 4.14-4.06 (m, 1H), 3.94 (s, 3H),1.93 (s, 3H), 1.33 (d, 3H), 0.55-0.43 (m, 3H).

Example 2544-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separation(Column: Chiralpak AS-H 5 μm, 20×250 mm, Flow 15 mL/min,heptane/EtOH/MeOH 80:10:10, Detection: UV 210/254 nm) of the racemicproduct of example 134. t_(R): 17.82 min (Column: Chiralpak AS-H,4.6×250 mm, Flow 1 mL/min. heptane/EtOH/MeOH 80:10:10, Detection: UV 210nm). t_(R): 0.98 min (LC-MS 2); ESI-MS: 541.1/543.2 [M+H]⁺ (LC-MS 2);¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.35 (s, 1H), 7.93 (s, 1H), 7.50-7.40(m, 4H), 7.37-7.31 (m, 2H), 7.21 (t, 1H), 6.58 (s, 1H), 4.10 (s, 2H),4.08 (s, 1H), 3.89 (s, 3H), 1.35 (d, 3H), 0.52 (d, 3H).

Example 2554-[(R)-5-(3-Chloro-2-fluoro-phenyl)-2-(2-cyanomethyl-5-methoxy-pyridin-4-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was obtained after preparative chiral HPLC separation(Column: Chiralpak AS-H 5 μm, 20×250 mm, Flow 15 mL/min,heptane/EtOH/MeOH 80:10:10, Detection: UV 210/254 nm) of the racemicproduct of example 134. t_(R): 23.77 min (Column: Chiralpak AS-H,4.6×250 mm, Flow 1 mL/min. heptane/EtOH/MeOH 80:10:10, Detection: UV 210nm). t_(R): 0.98 min (LC-MS 2); ESI-MS: 541.1/543.2 [M+H]⁺ (LC-MS 2);¹H-NMR (DMSO-d₆, 400 MHz) δ ppm 8.35 (s, 1H), 7.93 (s, 1H), 7.50-7.40(m, 4H), 7.37-7.31 (m, 2H), 7.21 (t, 1H), 6.58 (s, 1H), 4.10 (s, 2H),4.08 (s, 1H), 3.89 (s, 3H), 1.35 (d, 3H), 0.52 (d, 3H).

Example 2564-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-((R)-2-methoxy-1-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 256.1. After extraction,the product was purified by flash chromatography (heptane/EtOAc,1:1→0:100). t_(R): 1.00/1.02 min (LC-MS 2); ESI-MS: 563.2/565.1 [M+H]⁺(LC-MS 2); R_(f)=0.07 (heptane/EtOAc, 1:4).

Step 256.14-[2-Bromo-5-(3-chloro-2-fluoro-phenyl)-3-((R)-2-methoxy-1-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product from step 256.2. After extraction,the product was purified by flash chromatography (heptane/EtOAc,80:20→0:100). t_(R): 1.00/1.03 min (LC-MS 2); ESI-MS: 503.0/505.0 [M+H]⁺(LC-MS 2); R_(f)=0.14 (heptane/EtOAc, 1:2).

Step 256.22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 256.3. The product wasused without purification after the extraction. t_(R): 1.08 min (LC-MS2); ESI-MS: 519.0/521.0 [M+H]⁺ (LC-MS 2).

Step 256.32-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-cyano-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 256.4 and3-chloro-2-fluoroaniline. After completion, the reaction mixture wasextracted with H₂O and washed with a saturated NaHCO₃ solution. Theorganic was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (heptane/EtOAc, 80:20→52:48). t_(R):1.27 min (LC-MS 2); ESI-MS: 549.1/551.0 [M+H]⁺ (LC-MS 2); R_(f)=0.31(heptane/EtOAc, 1:1).

Step 256.42-Bromo-5-[(4-cyano-phenyl)-hydroxy-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step 111.6 but using the product from step 256.5. After extraction,the product was purified by flash chromatography (heptane/EtOAc,80:20→20:80). t_(R): 0.92 min (LC-MS 2); ESI-MS: 422.0/424.0 [M+H]⁺(LC-MS 2); R_(f)=0.33 (heptane/EtOAc, 1:2).

Step 256.52-Bromo-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylic acidethyl ester

The title compound was prepared in analogy to the procedure describedfor intermediate A but using the product from step 256.6. The reactionwas performed at rt for 6 days. The product was purified by flashchromatography (heptane/EtOAc, 100:0→40:60). t_(R): 0.76 min (LC-MS 2);ESI-MS: 291.0/293.0 [M+H]⁺ (LC-MS 2); R_(f)=0.0.41 (CH₂Cl₂/MeOH, 20:1).

Step 256.6 1-((R)-2-Methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor step 100.5 but using the product from step 111.9. After extraction,the residue was purified by flash chromatography (heptane/CH₂Cl₂/MeOH,100:0:0→85:14:1) to afford the title compound. t_(R): 0.60 (LC-MS 2);ESI-MS: 213.1 [M+H]⁺ (LC-MS 2).

Example 2574-[5-(5-chloro-2-methyl-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-((R)-2-methoxy-1-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 257.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the productwas purified by flash chromatography (heptane/EtOAc, 1:1→0:100). t_(R):1.02/1.04 min (LC-MS 2); ESI-MS: 559.1/561.2 [M+H]⁺ (LC-MS 2);R_(f)=0.09 (heptane/EtOAc, 1:4).

Step 257.14-[2-Bromo-5-(5-chloro-2-methyl-phenyl)-3-((R)-2-methyl-ethyl)-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product from step 257.2. After extraction,the product was purified by flash chromatography (heptane/EtOAc,80:20→0:100). t_(R): 1.03/1.04 min (LC-MS 2); ESI-MS: 499.0/501.0 [M+H]⁺(LC-MS 2); R_(f)=0.18 (heptane/EtOAc, 1:2).

Step 257.22-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 257.3. The product wasused without purification after the extraction. t_(R): 1.12 min (LC-MS2); ESI-MS: 517.0/519.0 [M+H]⁺ (LC-MS 2).

Step 257.32-Bromo-5-[(5-chloro-2-methyl-phenylamino)-(4-cyano-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 256.4 and5-chloro-2-methylaniline. After completion, the reaction mixture wasextracted with H₂O and washed with a saturated NaHCO₃ solution. Theorganic was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (heptane/EtOAc, 80:20→1:1). t_(R):1.30/1.32 min (LC-MS 2); ESI-MS: 545.1/547.1 [M+H]⁺ (LC-MS 2);R_(f)=0.30 (heptane/EtOAc, 1:1).

Example 2585-(3-Chloro-2-fluorophenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 258.1. After extraction,the product was purified by flash chromatography (heptane/EtOAc,1:1→5:95). t_(R): 1.14/1.16 min (LC-MS 2); ESI-MS: 572.1/574.1 [M+H]⁺(LC-MS 2) 15; R_(f)=0.09 (heptane/EtOAc, 1:4).

Step 258.12-Bromo-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product from step 258.2. After extraction,the product was purified by flash chromatography (heptane/EtOAc,80:20→25:75). t_(R): 1.15/1.17 min (LC-MS 2); ESI-MS: 512.0/514.0/516.0[M+H]⁺ (LC-MS 2); R_(f)=0.09 (heptane/EtOAc, 1:1).

Step 258.22-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 258.3. The product wasused without purification after the extraction. t_(R): 1.21 min (LC-MS2); ESI-MS: 530.1/531.9/534.0 [M+H]⁺ (LC-MS 2).

Step 258.32-Bromo-5-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 258.4 and3-chloro-2-fluoroaniline. After completion, the reaction mixture wasextracted with a saturated NaHCO₃ solution and washed with H₂O. Theorganic was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (heptane/EtOAc, 90:10→0:100). t_(R):1.40/1.46 min (LC-MS 2); ESI-MS: 558.0/560.0/562.0 [M+H]⁺ (LC-MS 2);R_(f)=0.37 (heptane/EtOAc, 1:1).

Step 258.42-Bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was obtained in analogy to the procedure describedfor intermediate B but using 4-chlorobenzaldehyde and the product fromstep 256.5. After completion, the reaction mixture was quenched with a1M NH₄Cl solution and extracted with EtOAc. The organic layer was dried(Na₂SO₄), filtered and concentrated. The residue was purified by flaschromatography (heptane/EtOAc, 80:20→20:80) to give the title compound.t_(R): 1.08 min (LC-MS 2); ESI-MS: 431.1/433.0 [M+H]⁺ (LC-MS 2).

Example 2595-(3-Chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 97.1 but using the product from step 259.1. After extraction,the product was purified by flash chromatography (heptane/EtOAc,1:1→0:100). t_(R): 1.16/1.18 min (LC-MS 2); ESI-MS: 572.1/574.1 [M+H]⁺(LC-MS 2); R_(f)=0.10 (heptane/EtOAc, 1:4).

Step 259.12-Bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-((R)-2-methoxy-1-methyl-ethyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 93.1 but using the product from step 259.2. After extraction,the product was purified by flash chromatography (heptane/EtOAc,80:20→25:75). t_(R): 1.17/1.20 min (LC-MS 2); ESI-MS: 511.9/514.0/516.0[M+H]⁺ (LC-MS 2); R_(f)=0.11 (heptane/EtOAc, 1:1).

Step 259.22-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step 93.2 but using the product from step 259.3. The product wasused without purification after the extraction. t_(R): 1.18 min (LC-MS2); ESI-MS: 530.0/532.0/534.0 [M+H]⁺ (LC-MS 2).

Step 259.32-Bromo-5-[(3-chloro-4-fluoro-phenylamino)-(4-chloro-phenyl)-methyl]-1-((R)-2-methoxy-1-methyl-ethyl)-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using the product from step 258.4 and3-chloro-4-fluoroaniline. After completion, the reaction mixture wasextracted with a saturated NaHCO₃ solution and washed with H₂O. Theorganic was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by flash chromatography (heptane/EtOAc, 90:10→0:100). t_(R):1.37/1.41 min (LC-MS 2); ESI-MS: 558.0/560.0/562.0 [M+H](LC-MS 2);R_(f)=0.37 (heptane/EtOAc, 1:1).

Example 2606-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(4-fluoro-3-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 260.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the productwas purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 40-60% in 16 min).t_(R): 1.16 min (LC-MS 2); ESI-MS: 522.2/524.2 [M+H]⁺ (LC-MS 2).

Step 260.12-Bromo-6-(4-chloro-phenyl)-5-(4-fluoro-3-methyl-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 260.2. The extraction wasperformed in CH₂Cl₂. The product was triturated in Et₂O to afford thetitle compound. t_(R): 1.18 min (LC-MS 2); ESI-MS: 462.1/464.1 [M+H]⁺(LC-MS 2).

Step 260.22-Bromo-5-[(4-chloro-phenyl)-(4-fluoro-3-methyl]-phenylamino)-methyl-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 260.3. t_(R): 1.19 min(LC-MS 2); ESI-MS: 480.0/482.0 [M+H]⁺ (LC-MS 2).

Step 260.32-Bromo-5-[(4-chloro-phenyl)-(4-fluoro-3-methyl]-phenylamino)-methyl-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 4-fluoro-3-methylaniline. Aftercompletion, the reaction mixture was extracted with HCl and washed witha saturated NaHCO₃ solution. The organic was dried (Na₂SO₄), filteredand concentrated. The product was used without further purification.t_(R): 1.37 min (LC-MS 2); ESI-MS: 508.1/510.1 [M+H]⁺ (LC-MS 2).

Example 2616-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5-(2-methoxy-5-methyl-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 261.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the productwas purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 40-60% in 16 min).t_(R): 1.14 min (LC-MS 2); ESI-MS: 534.2/536.2 [M+H]⁺ (LC-MS 2).

Step 261.12-Bromo-6-(4-chloro-phenyl)-1-isopropyl-5-(2-methoxy-5-methyl-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 261.2. The extraction wasperformed in CH₂Cl₂. The product was triturated in Et₂O to afford thetitle compound. t_(R): 1.16 min (LC-MS 2); ESI-MS: 474.0/476.0 [M+H]⁺(LC-MS 2).

Step 261.22-Bromo-5-[(4-chloro-phenyl)-(2-methoxy-5-methyl-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 261.3. t_(R): 1.21 min(LC-MS 2); ESI-MS: 492.0/494.1 [M+H]⁺ (LC-MS 2).

Step 261.32-Bromo-5-[(4-chloro-phenyl)-(2-methoxy-5-methyl-phenylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 2-methoxy-5-methylaniline.After completion, the reaction mixture was extracted with HCl and washedwith a saturated NaHCO₃ solution. The organic was dried (Na₂SO₄),filtered and concentrated. The product was used without furtherpurification. t_(R): 1.40 min (LC-MS 2); ESI-MS: 520.1/522.1 [M+H]⁺(LC-MS 2).

Example 2626-(4-Chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the product from step 262.1 and2,4-dimethoxypyrimidin-5-ylboronic acid. After extraction, the productwas purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 μm;0.1% TFA-water/acetonitrile; gradient acetonitrile 20-40% in 16 min).t_(R): 1.07 min (LC-MS 2); ESI-MS: 520.2/522.2 [M+H]⁺ (LC-MS 2).

Step 262.12-Bromo-6-(4-chloro-phenyl)-5-(2,6-dimethyl-pyrimidin-4-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor step 91.1 but using the product from step 262.2. The extraction wasperformed in CH₂Cl₂. The product was triturated in Et₂O to afford thetitle compound. t_(R): 1.10 min (LC-MS 2); ESI-MS: 460.0/462.0/464.1[M+H]⁺ (LC-MS 2).

Step 262.22-Bromo-5-[(4-chloro-phenyl)-(2,6-dimethyl-pyrimidin-4-ylamino)-methyl]-1-isopropyl-1H-imidazol-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 but using the product from step 262.3. After the acidicworkup, the product was in the aqueous layer. A saturated NaHCO₃solution was added to the aqueous layer and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to affordthe title compound. t_(R): 0.76 min (LC-MS 2); ESI-MS: 478.1/480.1[M+H]⁺ (LC-MS 2).

Step 262.32-Bromo-5-[(4-chloro-phenyl)-(2,6-dimethyl-pyrimidin-4-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 but using intermediate B and 4-amino-2,6-dimethylpyrimidine.After completion, the reaction mixture was extracted with 1M HCl andwashed with a saturated NaHCO₃ solution. The organic was dried (Na₂SO₄),filtered and concentrated. The product was used without furtherpurification. t_(R): 0.82 min (LC-MS 2); ESI-MS: 506.0/508.1 [M+H]⁺(LC-MS 2).

Example 263(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 193 (Column: IC 20 μm, 50×106 mm, Flow50 mL/min, heptane/EtOH/MeOH, 60:20:20, UV Detection 210 nm). t_(R):7.15 min (Column: Chiralpak IC, 20 μm, 4.6×250 mm. Flow: 2 mL/min.heptane/EtOH/MeOH, 75:15:15, UV Detection 220 nm).

Example 264(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 193 (Column: IC 20 μm, 50×106 mm, Flow50 mL/min, heptane/EtOH/MeOH, 60:20:20, UV Detection 210 nm). t_(R):18.22 min (Column: Chiralpak IC, 20 μm, 4.6×250 mm. Flow: 2 mL/min.heptane/EtOH/MeOH, 75:15:15, UV Detection 220 nm).

Example 265(S)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 192 (Column: IC 20 μm, 50×106 mm, Flow30 mL/min, heptane/EtOH/MeOH, 50:25:25, UV Detection 210 nm). t_(R):5.67 min (Column: Chiralpak IC, 20 μm, 4.6×250 mm. Flow: 2 mL/min.heptane/EtOH/MeOH, 50:25:25, UV Detection 220 nm).

Example 266(R)-2-(2-Amino-4-methoxy-pyrimidin-5-yl)-5-(3-chloro-2-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was obtained after preparative chiral SFC separationof the racemic product of example 192 (Column: IC 20 μm, 50×106 mm, Flow30 mL/min, heptane/EtOH/MeOH, 50:25:25, UV Detection 210 nm). t_(R):15.35 min (Column: Chiralpak IC, 20 μm, 4.6×250 mm. Flow: 2 mL/min.heptane/EtOH/MeOH, 50:25:25, UV Detection 220 nm).

Example 2676-(4-Chloro-phenyl)-5-(4-fluoro-3-methyl-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the products from steps 260.1 and 105.1. Afterextraction, the product was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 40-60% in 16 min). t_(R): 1.03 min (LC-MS 2); ESI-MS:521.2/523.2 [M+H]⁺ (LC-MS 2).

Example 2686-(4-Chloro-phenyl)-1-isopropyl-2-(5-methoxy-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-5-(2-methoxy-5-methyl-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 but using the products from steps 261.1 and 105.1. Afterextraction, the product was purified by preparative HPLC (Waters SunFire C18, 30×100 mm, 5 μm; 0.1% TFA-water/acetonitrile; gradientacetonitrile 40-60% in 16 min). The residue was dissolved in MeOH andfiltered over a Stratosphere SPE cartridge (PL-Thiol MP SPE) to removethe palladium. t_(R): 1.01 min (LC-MS 2); ESI-MS: 533.2/535.2 [M+H]⁺(LC-MS 2).

Example 2695-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from Intermediate J and(2-methoxy-pyrimidin-5-yl)boronic acid as starting materials. Thereaction was performed in presence of PdCl₂(dppf) (15 mol %) ascatalyst. t_(R): 0.90 min (LC-MS 4); ESI-MS: 527.0 [M+H]⁺ (LC-MS 4).¹H-NMR (DMSO-d6, 400 MHz) δ ppm 8.85 (s, 2H), 7.93 (d, J=6.60 Hz, 2H),7.51-7.43 (m, 2H), 7.39 (d, J=7.09 Hz, 2H), 6.51 (s, 1H), 4.42 (quin,J=6.66 Hz, 1H), 4.01 (s, 3H), 3.45 (s, 3H), 1.40 (d, J=6.72 Hz, 3H),0.67 (d, J=6.72 Hz, 3H).

Example 2705-(5-Chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-2-(2-methoxy-pyridine-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from intermediate J and(2-methoxy-pyridine-3-yl)boronic acid as starting materials. Thereaction was performed in presence of PdCl₂(PPh₃)₂ (20 mol %) ascatalyst. t_(R): 0.98 min (LC-MS 4); ESI-MS: 526.3 [M+H]⁺ (LC-MS 4).

Example 2716-(4-Chloro-2-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-pyrimidin-5-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from step 271.1 and(2-methoxy-pyrimidin-5-yl)boronic acid as starting materials. Thereaction was performed in presence of PdCl₂(dppf) (15 mol %) ascatalyst. t_(R): 0.87 min (LC-MS 4); ESI-MS: 505.3 [M+H]⁺ (LC-MS 4).

Step 271.12-Bromo-6-(4-chloro-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F using the product from step 271.2 as startingmaterial. t_(R): 0.92 min (LC-MS 4); ESI-MS: 477.2 [M+H]⁺ (LC-MS 4);1H-NMR (CDCl3, 400 MHz) δ ppm 7.35 (d, J=8.59 Hz, 2H), 7.06 (d, J=8.59Hz, 2H), 7.03 (d, J=2.34 Hz, 1H), 6.69 (dd, J=2.73 Hz, 1H), 5.50 (s,1H), 4.58 (quin, J=6.83 Hz, 1H), 3.40 (s, 3H); 2.05 (s, 3H), 1.45 (d,J=7.03 Hz, 3H), 0.82 (d, J=7.03 Hz, 3H).

Step 271.22-Bromo-5-[(-4-chloro-phenyl)-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 using the product from step 271.3. t_(R): 0.91 min (LC-MS4); ESI-MS: 495.2 [M+H]⁺ (LC-MS 4).

Step 271.32-Bromo-5-[(4-chloro-phenyl)-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-methyl]-1-isopropyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (product of step AK2) and the product from step 271.4as starting materials. t_(R): 1.09 min (LC-MS 4); ESI-MS: 523.2 [M+H]⁺(LC-MS 4).

Step 271.4 5-Amino-1,3-dimethyl-1H-pyridin-2-one

The compound prepared in step 271.5 (15.6 g, 93 mmol), was dissolved inTHF/MeOH (1:1, 400 mL) and hydrogenated over Pd—C (10% BASF 4505 D/R;2.0 g, 18 mmol) at rt for 4.5 h. The catalyst was removed by 2consecutive filtrations over celite and a pad of silica gel. Thefiltrate was concentrated and dried to give the title compound as abrown solid. t_(R): 0.23 min (LC-MS 4); ESI-MS: 139.1 [M+H]⁺ (LC-MS 4).¹H-NMR (DMSO-d6, 400 MHz) δ ppm 6.94 (s, 1H), 6.70 (s, 1H), 4.14 (bs,2H), 3.29 (s, 3H), 1.92 (s, 3H).

Step 271.5 1,3-Dimethyl-5-nitro-1H-pyridin-2-one

Methyl iodide (9.1 mL, 146 mmol) was added to a cold (0° C.) mixture of3-chloro-2-hydroxy-5-nitropyridine (15 g, 97 mmol) and K₂CO₃ (26.9 g,195 mmol) in DMF (100 mL). The reaction mixture was allowed to warm tort, stirred for 12 h, quenched by addition of water, and extracted withEtOAc. The organic phase was washed with brine, dried (Na₂SO₄),filtered, concentrated and dried to afford the title compound as a whitesolid. t_(R): 0.58 min (LC-MS 4); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 9.05(d, J=3.1 Hz, 1H), 8.09-7.98 (m, 1H), 3.45 (s, 3H), 2.05 (s, 3H).

Example 2726-(4-Chloro-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-2-(2-methoxy-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from step 271.1 and(2-methoxy-pyridine-3-yl)boronic acid as starting materials. Thereaction was performed in presence of PdCl₂(dppf) (15 mol %) ascatalyst. t_(R): 0.95 min (LC-MS 4); ESI-MS: 504.3 [M+H]⁺ (LC-MS 4).

Example 2736-(4-Chloro-2-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from step 271.1 and(2,4-dimethoxy-pyrimidin-5-yl)boronic acid as starting materials. t_(R):0.92 min (LC-MS 4); ESI-MS: 535.3 [M+H]⁺ (LC-MS 4).

Example 2746-(4-Chloro-2-phenyl)-1-cyclobutyl-2-(2,4-dimethoxy-pyrimidin-5-yl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor example 1 using the product from step 274.1 and(2,4-dimethoxy-pyrimidin-5-yl)boronic acid as starting materials. t_(R):0.96 min (LC-MS 4); ESI-MS: 547.3 [M+H]⁺ (LC-MS 4).

Step 274.12-Bromo-6-(4-chloro-phenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-1-cyclobutyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

The title compound was prepared in analogy to the procedure describedfor intermediate F using the product from step 274.2 as startingmaterial. t_(R): 0.96 min (LC-MS 4); ESI-MS: 489.2 [M+H]⁺ (LC-MS 4).

Step 274.22-Bromo-5-[(-4-chloro-phenyl)-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid

The title compound was prepared in analogy to the procedure describedfor step E1 using the product from step 274.3. t_(R): 0.94 min (LC-MS4); ESI-MS: 507.0 [M+H]⁺ (LC-MS 4).

Step 274.32-Bromo-5-[(4-chloro-phenyl)-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-ylamino)-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester

The title compound was prepared in analogy to the procedure describedfor step E2 using2-bromo-5-[(4-chlorophenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylicacid ethyl ester (product from step AK2) and the product from step 271.4as starting materials. t_(R): 1.13 min (LC-MS 4); ESI-MS: 535.3 [M+H]⁺(LC-MS 4).

The following examples have been synthesized according to describedprocedures herein or known literature methods using the appropriatestarting materials and methods known to the skilled person in the art:

example 275: 5-(5-Chloro-2-methyl- phenyl)-6-(5-chloro-pyridin-2-yl)-2-(2- dimethylamino-4- methoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.19 min (LC-MS 4); ESI-MS: 552.3 [M + H]⁺ (LC-MS 4) example 276:5-(5-Chloro-2-methyl- phenyl)-6-(5-chloro- pyridin-2-yl)-2-(2,4-dimethoxy-pyrimidin- 5-yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.11 min (LC-MS 4); ESi-MS: 539.2 [M + H]⁺ (LC-MS 4); 1H-NMR (800MHz, DMSO-d6) d ppm 8.60 (br, 1H), 8.50 (br, 1H), 7.95 (br, 1H), 7.80(br, 1H), 7.56-7.45 (m, 1H), 7.25-7.12 (m, 2H), 6.75-6.64 (m, 1H),4.6-4.2 (m, 1H),4.10- 4.05 (2s, 6H), 2.00 (s, 3H), 0.75-0.50 (m, 6H)example 277: 4-[5-(5-Chloro-1- methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2- (2-dimethylamino-4- methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo- 3,4,5,6-tetrahydro- pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro- benzonitrile

t_(R): 0.99 min (LC-MS 4); ESI-MS: 577.2 [M + H]⁺ (LC-MS 4); 1H-NMR (400MHz, DMSO-d6) δ ppm 0.55 (d, J = 6.65 Hz, 3H) 1.34 (d, J = 6.78 Hz, 3 H)3.19 (s, 6 H) 3.44 (s, 3 H) 3.89 (s, 3 H) 4.04- 4.19 (m, 1 H) 6.77 (s, 1H) 7.40-7.47 (m, 1 H) 7.81 (d, J = 2.89 Hz, 2 H) 7.95 (m, J = 2.80 Hz, 2H) 8.22 (s, 1 H) example 278: 4-[5-(5-Chloro-1- methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2- (2,4-dimethoxy- pyrimidin-5-yl)-3-isopropyl-6-oxo- 3,4,5,6-tetrahydro- pyrrolo[3,4-d]imidazol-4-yl]-2-fluoro- benzonitrile

t_(R): 0.90 min (LC-MS 4); ESI-MS: 564.2 [M + H]⁺ (LC-MS 4); 1H-NMR (400MHz, DMSO-d6) δ ppm 0.55 (d, J = 6.78 Hz, 3 H) 1.34 (d, J = 6.78 Hz, 3H) 3.45 (s, 3 H) 3.94 (s, 3 H) 3.99 (s, 3 H) 4.09-4.20 (m, 1 H) 6.79 (s,1 H) 7.38-7.49 (m, 1 H) 7.62 (s, 2 H) 7.96 (s, 2 H) 8.50 (s, 1 H)example 279: (S)-5-(5-Chloro-1- methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6- (4-chloro-phenyl)-2- (2,4-dihydroxy-pyrimidin-5-yl)-1- isopropyl-5,6-dihydro- 1H-pyrrolo[3,4-d]imidazol-4-one

t_(R): 0.80 min (LC-MS 4); ESI-MS: 527.3 [M + H]⁺ (LC-MS 4) example 280:(R)-5-(5-Chloro-1- methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2- dimethylamino-4- methoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

chiral separation of example 196: t_(R): 1.10 min (LC-MS 4); ESI-MS:568.3 [M + H]⁺ (LC-MS 4) example 281: (S)-5-(5-Chloro-1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-6- (4-chloro-phenyl)-2-(2-dimethylamino-4- methoxy-pyrimidin-5- yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol- 4-one

chiral separation of example 196: t_(R): 1.10 min (LC-MS 4); ESI-MS:568.3 [M + H]⁺ (LC-MS 4) example 282: (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3- yl)-6-(4-chloro- phenyl)-2-(2,4-dimethoxy-pyrimidin- 5-yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol- 4-one

chiral separation of example 122: t_(R): 0.94 min (LC-MS 4); ESI-MS:541.2 [M + H]⁺ (LC-MS 4) example 283: (R)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3- yl)-6-(4-chloro- phenyl)-2-(2,4-dimethoxy-pyrimidin- 5-yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol- 4-one

chiral separation from example 122: t_(R): 0.94 min (LC-MS 4); ESI-MS:541.2 [M + H]⁺ (LC-MS 4) example 284: 6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1- methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-2-(2,4-dimethoxy- pyrimidin-5-yl)-1- isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.02 min (LC-MS 4); ESI-MS: 573.2 [M + H]⁺ (LC-MS 4) example 285:6-(4-Chloro-3-fluoro- phenyl)-5-(5-chloro-1- methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2- (2-dimethylamino-4- methoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.12 min (LC-MS 4); ESI-MS: 586.1 [M + H]⁺ (LC-MS 4) example 286:5-(5-Chloro-1-methyl- 2-oxo-1,2-dihydro- pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4- dimethoxy-pyrimidin- 5-yl)-1-isopropyl-6-methyl-5,6-dihydro- 1H-pyrrolo[3,4- d]imidazol-4-one

Example 103 was in dissolved in THF (2mL) and immersed in a dry icebath. Then, 1.2 eq. KHMDS (1M in THF, Aldrich) was added and thereaction mixture was stirred for 15min at - 78° C. 3 eq. Mel (Aldrich)were added at −78° C. The dry ice bath was removed and the reactionmixture was allowed to warm up to room temperature. t_(R): 1.00 min(LC-MS 4); ESI-MS: 569.2 [M + H]⁺ (LC-MS 4) example 287:6-(4-Chloro-3-fluoro phenyl)-5-(5-chloro-1- methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2- (2-dimethylamino-4- methoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.06 min (LC-MS 4); ESI-MS: 586.1/588.2 [M + H]⁺ (LC-MS 4); 1H-NMR (400 MHz, DMSO- d6) δ ppm 0.57 (d, J = 6.53 Hz, 3 H) 1.35 (d, J =6.65 Hz, 3 H) 3.19 (s, 6 H) 3.46 (s, 3 H) 3.89 (s, 3 H) 4.03-4.19 (m, 1H) 6.44 (s, 1 H) 7.22- 7.35 (m, 1 H) 7.40-7.53 (m, 1 H) 7.58-7.69 (m, 1H) 7.85-8.01 (m, 2 H) 8.21 (s, 1 H) example 288: 4-[(R)-5-(5-Chloro-1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-2- (2-dimethylamino-4-methoxy-pyrimidin-5- yl)-3-isopropyl-6-oxo- 3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol- 4-yl]-2-fluoro- benzonitrile

chiral separation of example 277: t_(R): 0.99 min (LC-MS 4); ESI-MS:577.2 [M + H]⁺ (LC-MS 4); 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.48-0.60 (m,3 H) 1.29-1.38 (m, 3 H) 3.19 (s, 6 H) 3.44 (s, 3 H) 3.89 (s, 3 H)4.05-4.16 (m, 1 H) 6.73-6.80 (m, 1 H) 7.38-7.48 (m, 1 H) 7.55-7.64 (m,2H) 7.90- 7.99 (m, 2 H) 8.22 (s, 1 H) example 289: 4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-2- (2-dimethylamino-4-methoxy-pyrimidin-5- yl)-3-isopropyl-6-oxo- 3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol- 4-yl]-2-fluoro- benzonitrile

chirai separation of example 277: t_(R): 0.99 min (LC-MS 4); ESI-MS:577.1 [M + H]⁺ (LC-MS 4); 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.48-0.60 (m,3 H) 1.29-1.38 (m, 3 H) 3.19 (s, 6 H) 3.44 (s, 3 H) 3.89 (s, 3 H)4.05-4.16 (m, 1 H) 6.73-6.80 (m, 1 H) 7.38-7.48 (m, 1 H) 7.55-7.64 (m,2H) 7.90- 7.99 (m, 2 H) 8.22 (s, 1 H) example 290: 6-(4-Chloro-3-fluoro-phenyl)-5-(5-chloro-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-2-(2,4-dimethoxy- pyrimidin-5-yl)-1- isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.96 min (LC-MS 4); ESI-MS: 573.1 [M + H]⁺ (LC-MS 4); 1H-NMR (400MHz, DMSO-d6) δ ppm 0.57 (d, J = 6.78 Hz, 3 H) 1.36 (d, J = 6.78 Hz, 3H) 3.46 (s, 3 H) 3.95 (s, 3 H) 3.99 (s, 3 H) 4.08-4.21 (m, 1 H) 6.47 (s,1 H) 7.24-7.34 (m, 1 H) 7.41-7.53 (m, 1 H) 7.60-7.70 (m, 1 H) 7.87- 7.92(m, 1 H) 7.93- 7.99 (m, 1 H) 8.49 (s, 1 H) example 291:6-(4-Chloro-phenyl)-2- (2,4-dimethoxy- pyrimidin-5-yl)-5-(1,4-dimethyl-6-oxo-1,6- dihydro-pyridin-2-yl)-1- isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.95 min (LC-MS 4); ESI-MS: 535.1 [M + H]⁺ (LC-MS 4) example 292:6-(4-Chloro-phenyl)-2- (2,4-dimethoxy- pyrimidin-5-yl)-5-(1,5-dimethyl-2-oxo-1,2- dihydro-pyridin-3-yl)-1- isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.97 min (LC-MS 4); ESI-MS: 535.2 [M + H]⁺ (LC-MS 4); 1H-NMR (600MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.45- 7.42 (m, 3H); 7.30 (d, 2H), 7.22(s, 1H), 6.68 (s, 1H), 4.11 (m, 1H), 4.00-3.92 (m, 6H), 3.41 (s, 3H),1.95 (s, 3H), 1.36-0.49 (m, 6H) example 293: 6-(4-Chloro-phenyl)-2-(2-dimethylamino-4- methoxy-pyrimidin-5- yl)-5-(1,5-dimethyl-2-oxo-1,2-dihydro- pyridin-3-yl)-1- isopropyl-5,6-dihydro- 1H-pyrrolo[3,4-d]imidazol-4-one

t_(R): 1.06 min (LC-MS 4); ESI-MS: 548.2 [M + H]⁺ (LC-MS 4) example 294:5-(5-Chloro-1- difluoromethyl-6-oxo- 1,6-dihydro-pyridin-3-yl)-6-(4-chloro- phenyl)-2-(2,4- dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.07 min (LC-MS 4); ESI-MS: 591.1/593.2 [M + H]⁺ (LC-MS 4}example 295: 5-(5-Chloro-1-methyl- d3-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4- chloro-phenyl)-2-(2,4- dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6- dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.03 min (LC-MS 4); E8I-M5: 558.2/560.2 [M + H]⁺ (LC-MS 4)example 296: 5-(5-Chloro-1-ethyl-2- oxo-1,2-dihydro- pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4- dimethoxy-pyrimidin- 5-yl)-1-isopropyl-5,6-dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.09 min (LC-MS 4); ESI-MS: 569.2/571.2 [M + H]⁺ (LC-MS 4)example 297: 5-(5-Chloro-1-methyl- 2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4- chloro-2-methyl- phenyl)-2-(2,4-dimethoxy-pyrimidin- 5-yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol- 4-one

t_(R): 1.08 min (LC-MS 4); ESI-MS: 569.2/571.3 [M + H]⁺ (LC-MS 4)example 298: 5-(5-Chloro-1-methyl- 2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4- chloro-phenyl)-1- isopropyl-2-(4- methoxy-2-oxo-1,2-dihydro-pyrimidin-5- yl)-5,6-dihydro-1H- pyrrolo[3,4-d]imidazol- 4-one

t_(R): 0.84 min (LC-MS 4); ESI-MS: 541.4.2/543.2 [M + H]⁺ (LC-MS 4); 1H-NMR (400 MHz, DMSO- d6) δ ppm 11.87 (s, NH, 1H), 8.05 (s, 1H), 7.94 (d,1H), 7.51 (d, 1H), 7,42-7.30 (m, 4H), 6.69 (s, 1H), 4,19 (m, 1H), 3.82(s, 3H), 3.44 (s, 3H), 1.34/0.53 (2d, 6H) example 299:6-(4-Chloro-phenyl)-5- (2,6-dimethyl- pyrimidm-4-yl)-1- isopropyl-2-(5-methoxy-1-methyl-2- oxo-1,2-dihydro-pyridin- 4-yl)-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.89 min (LC-MS 2); ESI-MS: 519.2 [M + H]⁺ (LC-MS 2) example 300:6-(4-Chloro-phenyl)-2- (2,6-dimethoxy- pyrimidm-5-yl)-1- isopropyl-5-(3-methoxy-6-methyl- pyridazin-4-yl)-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

t_(R): 0.94 min (LC-MS 2); ESI-MS: 536.3/538.1 [M + H]⁺ (LC-MS 2)example 301: 5-(5-Chloro-2- methoxy-pyridin-3-yl)-6-(4-chloro-phenyl)-2- (2,4-dimethoxy- pyrimidin-5-yl)-1-isopropyl-5,6-dihydro- 1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.15 min (LC-MS 2); ESI-MS: 555.1/557.2 [M + H]⁺ (LC-MS 2)example 302: 6-(4-Chloro-phenyl)-2- (2-dimethylamino-4-methoxy-pyrimidin-5- yl)-1-isopropyl-5-(3- methoxy-6-methyl-pyridazin-4-yl)-5,6- dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.06 min (LC-MS 2); ESI-MS: 549.2 [M + H]⁺ (LC-MS 2) example 303:6-(4-Chloro-2-fluoro- phenyl)-5-(3-chloro-2- fluoro-phenyl)-2-(2-dimethylamino-4- methoxy-pyrimidin-5- yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.27 min (LC-MS 2); ESI-MS: 573.3/575.2 [M + H]⁺ (LC-MS 2)example 304: 6-(4-Chloro-2-fluoro- phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-2- (2,4-dimethoxy-pyrimidin-5-yl)-1- isopropyl-5,6-dihydro- 1H-pyrrolo[3,4-d]imidazol-4-one

t_(R): 1.02 min (LC-MS 2); ESI-MS: 573.1/575.1 [M + H]⁺ (LC-MS 2)example 305: 6-(4-Chloro-2-fluoro- phenyl)-5-(5-chloro-1-methyl-2-oxo-1,2- dihydro-pyridin-3-yl)-2- (2,4-dimethylamino-4-methoxy-pyrimidin-5- yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4-d]imidazol-4-one

t_(R): 1.12 min (LC-MS 2); ESI-MS: 586.1/588.1 [M + H]⁺ (LC-MS 2)example 306: 6-(4-Chloro-phenyl)-2- (2-dimethylamino-4-methoxy-pyrimidin-5- yl)-5-(4-fluoro-2,5- dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6- dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.14 min (LC-MS 2); ESI-MS: 539.3 [M + H]⁺ (LC-MS 2) example 307:(S)-5-(5-Chloro-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2- (2,4-dimethoxy- pyrimidm-5-yl)-1-isopropyl-5,6-dihydro- 1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.95 min (LC-MS 2); ESI-MS: 555.2/557.2 [M + H]⁺ (LC-MS 2);t_(R): 2.32 min (Column: Chiralcel OD H 4.6 x 250 mm. Flow 3.0 mL/min.scCO₂/MeOH 65:35. Detection: UV 210 nM), >99% ee example 308:(R)-5-(5-Chloro-1- methyl-6-oxo-1,6- dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2- (2,4-dimethoxy- pyrimidin-5-yl)-1-isopropyl-5,6-dihydro- 1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.95 min (LC-MS 2); ESI-MS: 555.1/557.1 [M + H]⁺ (LC-MS 2);t_(R): 5.13 min (Column: Chiralcel OD H 4.6 x 250 mm. Flow 3.0 mL/min.scCO₂/MeOH 65:35. Detection: UV 210 nM), >99% ee example 309:6-(4-Chloro-phenyl)-5- (5-cyclopropyl-4-fluoro- 2-methyl-2H-pyrazol-3-yl)-2-(2,4-dimethoxy- pyrimidin-5-yl)-1- isopropyl-5,6-dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 1.13 min (LC-MS 4); ESI-MS: 552.2 [M + H]⁺ (LC-MS 4) example 310:6-(4-Chloro-phenyl)-5- (5-cyclopropyl-4-fluoro- 2-methyl-2H-pyrazol-3-yl)-1-isopropyl-2-(5- methoxy-1-methyl-2- oxo-1,2-dihydro-pyridin-4-yl)-5,6- dihydro-1H-pyrrolo[3,4- d]imidazol-4-one

t_(R): 0.98 min (LC-MS 4); ESI-MS: 551.2 [M + H]⁺ (LC-MS 4) example 311:4-{5-(3-Chloro-2-fluoro- phenyl)-2-[2-(1,1- dioxo-1-thiomorpholin-4-yl)-4-methoxy- pyrimidin-5-yl]-3- isopropyl-6-oxo- 3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol- 4-yl}-benzonitrile

t_(R): 1.00 min (LC-MS 4); ESI-MS: 636.2, 638.2 [M + H]⁺ (LC-MS 4)example 312: 4-{5-(3-Chloro-2-fluoro- phenyl)-2-[2-((S)-3-hydroxy-piperidin-1-yl)- 4-methoxy-pyrimidin-5- yl]-3-isopropyl-6-oxo-3,4,5,6-tetrahydro- pyrrolo[3,4-d]imidazol- 4-yl}-benzonitrile

t_(R): 1.02 min (LC-MS 4); ESI-MS: 602.2, 604.3 [M + H]⁺ (LC-MS 4)example 313: 2-(2-amino-4- methoxypyrimidin-5- yl)-5-(3-chloro-4-fluorophenyl)-6-(4- chlorophenyl)-1-((R)-1- methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 1.06/1.08 min (LC-MS 2); ESI-MS: 557.1/559.1 [M + H]⁺ (LC-MS 2);Rf = 0.19 (EtOAc—MeOH, 20:1). example 314: 2-(2-amino-4-methoxypyrimidin-5- yl)-5-(5-chloro-2- methylphenyl)-6-(4-chlorophenyl)-1-((R)-1- methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

t_(R): 107/1.09 min (LC-MS 2); ESI-MS: 553.1/555.1 [M + H]⁺ (LC-MS 2);Rf = 0.09 (EtOAc—MeOH, 98:2). example 315: (R)-5-(3-chloro-2-fluorophenyl)-6-(4- chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-1-((R)-1- hydroxypropan-2-yl)- 5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

t_(R): 1.01 min (LC-MS 2); ESI-MS: 558.1/560.0 [M + H]⁺ (LC-MS 2)example 316: (S)-5-(3-chloro-2- fluorophenyl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5- yl)-1-((R)-1-hydroxypropan-2-yl)- 5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 1.04 min (LC-MS 2); ESI-MS: 558.1/560.0 [M + H]⁺ (LC-MS 2)example 317: (S)-5-(3-chloro-4- fluorophenyl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5- yl)-1-((R)-1-methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 1.19 min (LC-MS 2); ESI-MS: 572.0/574.0 [M + H]⁺ (LC-MS 2); Rf =0.10 (heptane- EtOAc, 1:4); 1H-NMR (DMSO- d6, 600 MHz) δ ppm 8.43(s,1H), 7.84 (d, 1H), 7.54 (m, 1H), 7.42-7.32 (m, 5H), 6.64 (s, 1H),4.16 (m, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.62 (m, 1H), 3.41 (m, 1H),3.22 (s, 3H), 0.52 (d, 3H). example 318: (R)-5-(3-chloro-4-fluorophenyl)-6-(4- chlorophenyl)-2-(2,4- dimethoxypyrimidin-5-yl)-1-((R)-1- methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

t_(R): 1.17 min (LC-MS 2); ESI-MS: 572.0/574.0 [M + H]⁺ (LC-MS 2); Rf =0.10 (heptane- EtOAc, 1:4). example 319: 5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin- 3-yl)-6-(4- chlorophenyl)-2-(2,4-dimethoxypyrimidin-5- yl)-1-((R)-1- methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 0.91/0.93 min (LC- MS 2); ESI-MS: 585.0/ 587.0 [M + H]⁺ (LC-MS2); Rf = 0.07/0.10 (DCM— MeOH, 20:1). example 320:5-(5-chloro-1-methyl-2- oxo-1,2-dihydropyridin- 3-yl)-6-(4-chlorophenyl)-2-(2,4- dimethoxypyrimidin-5- yl)-1-((R)-1-methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 0.99/1.01 min (LC- MS 2); ESI-MS: 585.0/ 587.0 [M + H]⁺ (LC-MS2); Rf = 0.07/0.10 (DCM— MeOH, 20:1). example 321:5-(5-chloro-1-methyl-6- oxo-1,6-dihydropyridin- 3-yl)-6-(4-chlorophenyl)-2-(2- (dimethylamino)-4- methoxypyrimidin-5- yl)-1-((R)-1-methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 0.99/1.02 min (LC- MS 2); ESI-MS: 598.1/ 600.1 [M + H]⁺ (LC-MS2); Rf = 0.18/0.23 (EtOAc— MeOH, 10:1). example 322: (S)-5-(5-chloro-1-methyl-2-oxo-1,2- dihydropyridin-3-yl)-6- (4-chlorophenyl)-2-(2,4-dimethoxy-d6- pyrimidin-5-yl)-1-((R)- 1-methoxypropan-2- yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 1.01 min (LC-MS 2); ESI-MS: 561.2/563.2 [M + H]⁺ (LC-MS 2); 1H-NMR (DMSO-d6, 600 MHz) δ ppm 8.49 (s, 1H), 7.91 (s, 1H), 7.50 (s, 1H),7.42 (m, 2H), 7,33 (m, 2H), 6.72 (s, 1H), 4.12 (m, 1H), 3.44 (s, 3H),1.34 (d, 3H), 0.52 (d, 3H). example 323: (S)-5-(5-chloro-1-methyl-6-oxo-1,6- dihydropyridin-3-yl)-6- (4-chlorophenyl)-2- (2,4-dimethoxypyrimidin-5- yl)-1-((R)-1- methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 0.94 min (LC-MS 2); ESI-MS: 585.1/587.1 [M + H]⁺ (LC-MS 2); 1H-NMR (DMSO-d6, 600 MHz) δ ppm 8.44 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H),7.44 (d, 2H), 7.35 (bs, 2H), 6.30 (s, 1H), 4.17 (m, 1H), 3.98 (s, 3H),3.92 (s, 3H), 3.53 (m, 1H), 3.45 (s, 3H), 3.40 (m, 1H), 3.22 (s, 3H),0.55 (d, 3H) example 324: (R)-5-(5-chloro-1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-6- (4-chlorophenyl)-2- (2,4- dimethoxypyrimidin-5-yl)-1-((R)-1- methoxypropan-2-yl)- 5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

t_(R): 0.91 min (LC-MS 2): ESI-MS: 585.1/587.1 [M + H]⁺ (LC-MS 2)example 325: (S)-5-(5-chloro-1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-6- (4-chlorophenyl)-2-(2- (dimethylamino)-4-methoxypyrimidin-5- yl)-1-((R)-1- methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 1.03 min (LC-MS 2); ESI-MS: 598.0/600.0 [M + H]⁺ (LC-MS 2); 1H-NMR (DMSO-d6, 600 MHz) δ ppm 8.17 (s, 1H), 7.87 (m, 2H), 7.43 (m, 2H),7.34 (bs, 2H), 6.28 (s, 1H), 4.13 (m, 1H), 3.87 (s, 3H), 3.54 (m, 1H),3.45 (s, 3H), 3.41 (m, 1H), 3.22 (s, 3H), 3.18 (6H, s), 0.55 (d, 3H)example 326: (R)-5-(5-chloro-1- methyl-6-oxo-1,6-dihydropyridin-3-yl)-6- (4-chlorophenyl)-2-(2- (dimethylamino)-4-methoxypyrimidin-5- yl)-1-((R)-1- methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4- d]imidazol-4(1H)-one

t_(R): 0.91 min (LC-MS 2); ESI-MS: 598.0/600.0 [M + H]⁺ (LC-MS 2)

Selected compounds have been crystallized and further characterized. Theexperimental procedures and the instrument and method description areoutlined below:

Instrument Name: X-Ray Diffractometer

Model: D8 Advance

Manufacturer: Bruker AXS GMBH

Wavelength: 1.5406 A (Cu)

Generator setting: 30 Kv; 40 mA

Monochromator

Detector PSD-Lynx Eye

Experiment Method:

2-Theta start: 2.0 degree

2-Theta end: 40.0 degree

Integration stepsize: 0.0157 degree

Scan Time: 13.02 min

Temperature: room temperature

The following methods A to G below disclose methods to obtain certaincrystalline forms of Example compounds described herein.

A.4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile(Example 79) Crystalline Form A

The compound of Example 79 was triturated in diisopropylether andstirred overnight at rt. The suspension was filtered, and the colorlesssolid was dried under high vacuum overnight at rt to give crystallinematerial Form A.

Angle d value 2-Theta ° Angstrom Intensity 6.54 13.50 Medium 10.00 8.83Low 10.88 8.13 Low 14.29 6.19 Medium 15.72 5.63 Medium 16.78 5.28 High17.82 4.97 Medium 19.41 4.57 High 20.10 4.41 Medium 20.67 4.29 Medium23.65 3.76 High 25.82 3.44 High

B.4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile(Example 199) Crystalline Form A

The compound of Example 199 (2.20 g) was dissolved in 25 ml ethylacetate under stirring. Colorless solid was formed again and thesuspension was stirred for one additional hour. Under stirring 25 mldiisopropyl ether were added and the mixture was stirred for 5 minutes.The suspension was filtered and the residue was washed with diisopropylether (two times 10 ml). The colorless solid was dried at the highvacuum pump over night at 50° C. to obtain 2.03 g colorless crystalsForm A.

Angle d value 2-Theta ° Angstrom Intensity 6.25 14.13 Medium 9.44 9.36Low 10.34 8.55 Medium 14.02 6.31 Low 14.83 5.97 Medium 15.33 5.77 Medium15.84 5.59 Medium 16.96 5.22 High 19.16 4.63 Medium 19.50 4.55 Medium20.94 4.24 Medium 22.32 3.98 Medium 25.05 3.55 Medium 25.74 3.46 Medium27.33 3.26 Low

C.(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one(Example 102) Crystalline Form A (Ethanol Solvate)

The compound of Example 102 (2.02 g, ee 99.8%) was taken up in ethanoland the mixture was heated to reflux under stirring to get a clearsolution (total amount ethanol used: 48 ml). The clear yellowishsolution was allowed to cool down to ambient temperature under stirringovernight. The precipitate was filtered off and dried under high vacuumto obtain 1.78 g colorless solid Form A ethanol solvate. The solidcontains 7.5% ethanol (1 equivalent), seen by 1H-NMR.

Angle d value 2-Theta ° Angstrom Intensity 9.44 9.36 Low 9.89 8.94 High10.69 8.27 Low 12.33 7.17 Medium 14.61 6.06 Medium 16.21 5.46 Medium16.66 5.32 Medium 17.50 5.07 Medium 17.78 4.98 Medium 19.83 4.47 Medium20.56 4.32 Medium 22.35 3.97 Medium 22.98 3.87 Medium 25.81 3.44897Medium

D.(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one(Example 102) Crystalline Form B (Succinic Acid Co-Crystal)

The compound of Example 102 (100 mg) was dissolved in 2 ml ethyl acetateand warmed to 55° C. 25.5 mg (1.2 equivalent) succinic acid was added tothe solution and the mixture was cooled down to 5° C. and warmed back to55° C. for 4 times in one day. The formed precipitate was filtered offand dried at 40° C. under vacuum for 4 hours to yield the product ascolorless powder Form B succinic acid form (stoichiometry by NMR 1.04succinic acid to I free form).

Angle d value 2-Theta ° Angstrom Intensity 9.037 9.78 High 11.64 7.60Low 14.55 6.08 Low 15.14 5.85 Low 15.60 5.68 Low 16.55 5.35 Low 17.275.13 High 19.52 4.54 Medium 19.87 4.46 Low 20.85 4.26 Medium 21.14 4.20Medium 23.42 3.80 Medium 23.67 3.76 Medium 24.54 3.62 Medium 26.95 3.31Medium

E.(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one(Example 102) Crystalline Form C (Hydrate)

The compound of Example 102 (10 mg) was dissolved in 0.1 ml IPA(isopropyl alcohol) under shaking or heating at 50° C. White solid wasformed after sonication for 5 seconds and the suspension was stirred for2 days at room temperature. The solid was separated by centrifugationand dried at 40° C. in vacuum for 2 days to obtain IPA solvate. Said IPAsolvate (8 mg) was suspended in 0.2 ml MeOH:H₂O (1:9, v/v) understirring for 2 days at room temperature. The resulting solid wasseparated by centrifugation and dried in air for 2 hours to yield theForm C hydrate as white powder.

Alternatively, ethanol solvate from Method C above was dissolved inmethanol, and clear solution obtained after 10 min with continuousstirring at room temperature. Water was added and precipitation observedafter 10 min at room temperature, then further water was added whilestirring for up to 24 hours. The resulting solid was separated bycentrifugation, then dried at room temperature to yield the Form Chydrate.

Angle d value 2-Theta ° Angstrom Intensity 8.14 10.86 Low 10.09 8.76Medium 11.92 7.42 Low 14.52 6.10 Medium 14.88 5.95 Medium 16.93 5.23Medium 17.56 5.05 Medium 17.98 4.93 Low 19.18 4.62 Medium 20.46 4.34High 20.87 4.25 Medium 21.86 4.06 Medium 25.00 3.56 High 25.68 3.47Medium 25.95 3.43 Low 28.57 3.12 Medium 32.17 2.78 Medium

F.4-[(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile(Example 160) Crystalline Form A

The compound of Example 160 (473 mg) was triturated in diethylether andstirred. After 1 hour, the solid was filtered off and dried to affordcrystalline colorless material Form A.

Angle d value 2-Theta ° Angstrom Intensity 7.57 11.67 Medium 9.11 9.70Medium 10.25 8.62 High 11.16 7.92 High 12.18 7.26 Medium 14.47 6.12Medium 17.38 5.10 High 18.37 4.83 High 19.03 4.66 Medium 20.78 4.27 High21.94 4.05 Medium 23.53 3.78 Medium 24.09 3.69 Medium

G.(S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Example 317) Crystalline Form A

The compound of Example 317 (486 mg, 0.849 mmol) was triturated for 2hrs in 24 ml of a mixture of water/ethanol (95/5), then sonicated andafterwards stirred at rt for 4 days. The solid was filtered off, washedwith water and dried under high vacuum at 50° C. for 24 hrs to yield 416mg of colorless solid Form A.

Angle d value 2-Theta ° Angstrom Intensity 6.76 13.07 Low 8.48 10.42 Low9.98 8.85 Medium 12.56 7.04 Medium 14.58 6.07 High 14.95 5.92 Medium15.55 5.70 Medium 16.62 5.33 Low 17.08 5.19 High 17.44 5.08 High 19.724.50 Medium 23.83 3.73 Medium 25.78 3.45 Medium 26.26 3.39 Medium

Described below are a number of embodiments (EX) of the first aspect ofthe invention.

Ex1

In one embodiment of the invention there is provided a crystalline formof any of:

-   4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one-   4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile-   (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one

Ex2

A crystalline form according to EX1, consisting essentially of saidform, as described herein.

Ex3

A crystalline form according to EX1, wherein said form as describedherein, is in substantially pure form.

Ex4

The crystalline form A of4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile,according to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 6.54±0.2, 14.29±0.2, 15.72±0.2, 16.78±0.2,17.82±0.2, 19.41±0.2, 20.10±0.2°, 20.67±0.2, 23.65±0.2 and 25.82±0.2, ata temperature of about 22° C., in particular 16.78±0.2, 19.41±0.2,23.65±0.2 and 25.82±0.2.

Ex5

The crystalline form A of4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrileaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 6.25±0.2, 10.34±0.2, 14.83±0.2, 15.33±0.2,15.84±0.2, 19.16±0.2, 19.50±0.2°,20.94±0.2, 22.32±0.2, 25.05±0.2 and25.74±0.2, at a temperature of about 22° C.

Ex6

The crystalline form A of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-oneaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 9.89±0.2, 12.33±0.2, 14.61±0.2, 16.21±0.2,16.66±0.2, 17.50±0.2, 17.78±0.2, 19.83±0.2, 20.56±0.2, 22.35±0.2,22.98±0.2° at a temperature of about 22° C.

Ex7

The crystalline form B of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-oneaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 9.04±0.2, 17.27±0.2, 19.52±0.2, 20.85±0.2,21.14±0.2, 23.42±0.2, 23.67±0.2, 24.54±0.2, 26.95±0.2° at a temperatureof about 22° C.

Ex8

The crystalline form C of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-oneaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction patter comprising 4 or more 2 theta values selected from thegroup consisting of 10.09±0.2, 14.52±0.2, 14.88±0.2, 16.93±0.2,17.56±0.2, 19.18±0.2, 20.46±0.2, 20.87±0.2, 21.86±0.2, 25.00±0.225.68±0.2, 28.57±0.2, 32.17±0.2° at a temperature of about 22° C.

Ex9

The crystalline form A of4-[(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-2-(2-dimethylamino-4-methoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrileaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 7.57±0.2, 9.11±0.2, 10.25±0.2, 11.16±0.2,12.18±0.2, 14.47±0.2, 17.38±0.2, 18.37±0.2, 19.03±0.2, 20.78±0.2,21.94±0.2, 23.53±0.2 and 24.09±0.2° at a temperature of about 22° C.

Ex10

The crystalline form A of(S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-oneaccording to any one of EX1 to EX3, characterized by a x-ray powderdiffraction pattern comprising 4 or more 2 theta values selected fromthe group consisting of 9.98±0.2, 12.56±0.2, 14.58±0.2, 14.95±0.2,15.55±0.2, 17.08±0.2, 17.44±0.2, 19.72±0.2, 23.83±0.2, 25.78±0.2,26.26±0.2° at a temperature of about 22° C., in particular 14.58±0.2,17.08±0.2 and 17.44±0.2.

In another aspect of the invention, there is provided any compound, saltor solid form thereof, as defined herein.

Biological Data:

Time Resolved Fluorescence Energy Transfer (TR-FRET) Assay

The inhibition of p53-MDM2 and p53-MDM4 interactions is measured by timeresolved fluorescence energy transfer (TR-FRET). Fluorescence energytransfer (or Foerster resonance energy transfer) describes an energytransfer between donor and acceptor fluorescent molecules. For thisassay, human MDM2 protein (amino acids 2-188) and human MDM4 protein(amino acids 2-185), tagged with a C-terminal biotin moiety, are used incombination with a Europium labeled streptavidin (Perkin Elmer, Inc.,Waltham, Mass., USA) serving as the donor fluorophore. The p53 derived,Cy5 labeled peptide Cy5-TFSDLWKLL (p53 aa18-26) is the energy acceptor.Upon excitation of the donor molecule at 340 nm, binding interactionbetween MDM2 or MDM4 and the p53 peptide induces energy transfer andenhanced response at the acceptor emission wavelength at 665 nm.Disruption of the formation of the p53-MDM2 or p53-MDM4 complex due toan inhibitor molecule binding to the p53 binding site of MDM2 or MDM4results in increased donor emission at 620 nm. The ratiometric FRETassay readout is calculated from the raw data of the two distinctfluorescence signals measured in time resolved mode (fluorescence 665nm/fluorescence 620 nm×1000).

The test is performed in white 384-well plates (Greiner Bio-One,reference 781207) in a total volume of 60 μL by adding 1 μL of compoundstested at different concentrations diluted in 100% DMSO (1.7% final DMSOconcentration) in reaction buffer (PBS, 125 mM NaCl, 0.001% Novexin(consists of carbohydrate polymers), designed to increase the solubilityand stability of proteins; Expedeon Ltd., Cambridgeshire, UnitedKingdom), 0.01% Gelatin, 0.01% 0.2%, Pluronic F-127 (block copolymerfrom ethylenoxide and propyleneoxide), 1 mM DTT). After addition of 0.1nM MDM2-biotinylated or 2.5 nM MDM4-biotinylated (internal preparations,both MDM2 and MDM4 are biotinylated at the C-terminal of the peptideconstruct), and 0.1 nM (p53-MDM2 assay) or 0.625 nM (p53-MDM4 assay)Europium labeled streptavidin (Perkin Elmer), respectively, the solutionis pre-incubated for 15 minutes at room temperature, then 10 nM Cy5-p53peptide (internal preparation, the Cy5 dye is directly bound to theN-terminal part of p53 peptide construct) is added before an incubationat room temperature for 15 minutes prior to reading the plate. Formeasurement of samples, a Victor II microplate reader (Perkin Elmer) isused with the following settings in the p53-MDM4 assay: Excitation 340nm, Emission Donor 620 nm and Emission Acceptor 665 nm. Tecan genios Prois used as a microplate reader for the fluorescence measurements in thep53-MDM2 assay. IC₅₀ values are calculated by curve fitting using XLfit.If not specified, reagents are purchased from Sigma-Aldrich Chemie GmBH,Buchs, Switzerland.

IC₅₀ Example p53-MDM2 (nM) p53-MDM4 (μM) 1 0.17 0.468 2 0.17 0.411 30.65 0.703 4 0.14 0.175 5 0.25 0.534 6 n.d. 7.09  7 0.17 0.530 8 2.27n.d. 9 0.07 0.229 10 0.20 0.179 11 0.15 0.120 12 0.15 0.217 13 0.18 n.d.14 0.18 n.d. 15 0.22 0.79  16 0.09 n.d. 17 0.07 n.d. 18 0.14 0.34  190.15 n.d. 20 0.17 0.76  21 0.12 n.d. 22 0.13 n.d. 23 0.13 n.d. 24 0.20n.d. 25 0.16 n.d. 26 0.23 n.d. 27 0.137 n.d. 28 0.62 n.d. 29 0.22 n.d.30 0.37 n.d. 31 0.19 n.d. 32 0.19 n.d. 33 0.47 n.d. 34 0.65 n.d. 35 0.16n.d. 36 0.13 n.d. 37 0.27 n.d. 38 0.19 n.d. 39 0.17 n.d. 40 0.74 n.d. 410.15 n.d. 42 0.11 n.d. 43 0.27 3.38  44 0.60 7.8  45 2.95 31.5   46 0.16n.d. 47 0.40 n.d. 48 0.34 n.d. 49 0.42 n.d. 50 0.39 n.d. 51 0.16 n.d. 520.17 n.d. 53 1.03 n.d. 54 0.31 n.d. 55 0.19 n.d. 56 1.21 n.d. 57 0.28n.d. 58 0.20 n.d. 59 0.20 n.d. 60 0.18 n.d. 61 0.13 n.d. 62 0.21 n.d. 630.17 n.d. 64 0.41 0.71  65 3.58 n.d. 66 0.23 n.d. 67 1.15 n.d. 68 0.71n.d. 69 0.18 0.49  70 0.14 n.d. 71 n.d. 11.42  72 1.02 n.d. 73 0.42 n.d.74 0.34 n.d. 75 0.07 n.d. 76 14.7 n.d. 77 0.19 n.d. 78 2.07 n.d. 79 0.36n.d. 80 0.27 n.d. 81 0.35 n.d. 82 0.4 n.d. 83 1.47 n.d. 84 1.54 n.d. 8511.8 n.d. 86 4.6 n.d. 87 31.7 n.d. 88 3.6 n.d. 89 0.04 n.d. 90 1.10 n.d.91 0.45 n.d. 92 1.64 n.d. 93 0.36 n.d. 94 0.32 n.d. 95 1.31 n.d. 96 0.62n.d. 97 n.d. n.d. 98 15.1 n.d. 99 11.8 n.d. 100 0.64 n.d. 101 0.34 n.d.102 0.23 n.d. 103 299.7 n.d. 104 5.61 n.d. 105 0.31 n.d. 106 0.28 n.d.107 0.32 n.d. 108 1.10 n.d. 109 0.35 n.d. 110 0.23 n.d. 111 0.25 n.d.112 0.56 n.d. 113 0.11 n.d. 114 0.70 n.d. 115 0.62 n.d. 116 2.3 n.d. 1170.09 n.d. 118 4.29 n.d. 119 4.97 n.d. 120 0.57 n.d. 121 0.26 n.d. 1220.25 n.d. 123 3.44 n.d. 124 2.33 n.d. 125 4.99 n.d. 126 0.24 n.d. 1270.14 n.d. 128 3.79 n.d. 129 0.41 n.d. 130 0.18 n.d. 131 1.65 n.d. 1321.93 n.d. 133 0.65 n.d. 134 0.69 n.d. 135 0.27 n.d. 136 0.20 n.d. 1371.62 n.d. 138 4.74 n.d. 139 0.66 n.d. 140 1.32 n.d. 141 0.20 n.d. 1420.36 n.d. 143 105.6 n.d. 144 1.70 n.d. 145 2.80 n.d. 146 2.4 n.d. 1470.66 n.d. 148 1.83 n.d. 149 1.74 n.d. 150 2.18 n.d. 151 1.95 n.d. 1521.01 n.d. 153 0.38 n.d. 154 0.17 n.d. 155 0.17 n.d. 156 1.27 n.d. 1570.27 n.d. 158 0.14 n.d. 159 1.35 n.d. 160 0.33 n.d. 161 153.2 n.d. 1620.32 n.d. 163 39.6 n.d. 164 0.10 n.d. 165 0.32 n.d. 166 214.3 n.d. 1670.44 n.d. 168 15.8 n.d. 169 0.11 n.d. 170 0.16 n.d. 171 0.52 n.d. 1720.29 n.d. 173 0.08 n.d. 174 0.11 n.d. 175 0.10 n.d. 176 0.68 n.d. 1770.19 n.d. 178 43.4 n.d. 179 6.83 n.d. 180 102.7 n.d. 181 1.32 n.d. 1820.18 n.d. 183 0.38 n.d. 184 0.31 n.d. 185 0.36 n.d. 186 0.27 n.d. 1870.57 n.d. 188 0.33 n.d. 189 70.5 n.d. 190 0.13 n.d. 191 0.27 n.d. 1920.42 n.d. 193 0.49 n.d. 194 0.17 n.d. 195 0.15 n.d. 196 0.16 n.d. 1970.11 n.d. 198 0.20 n.d. 199 0.16 n.d. 200 0.29 n.d. 201 0.26 n.d. 2020.19 n.d. 203 0.68 n.d. 204 68.6 n.d. 205 0.11 n.d. 206 82.5 n.d. 2071.05 n.d. 208 0.15 n.d. 209 0.09 n.d. 210 0.63 n.d. 211 0.39 n.d. 212n.d n.d. 213 0.54 n.d. 214 0.50 n.d. 215 0.43 n.d. 216 0.29 n.d. 21713.4 n.d. 218 0.05 n.d. 219 0.25 n.d. 220 0.24 n.d. 221 0.24 n.d. 22236.8 n.d. 223 0.09 n.d. 224 5.81 n.d. 225 5.39 n.d. 226 0.08 n.d. 2270.37 n.d. 228 0.08 n.d. 229 0.77 n.d. 230 0.56 n.d. 231 0.77 n.d. 2320.97 n.d. 233 6.60 n.d. 234 0.29 n.d. 235 0.21 n.d. 236 n.d n.d. 2372.22 n.d. 238 1.09 n.d. 239 0.54 n.d. 240 1.2 n.d. 241 0.41 n.d. 2420.27 n.d. 243 142.6 n.d. 244 21.5 n.d. 245 0.12 n.d. 246 0.15 n.d. 2470.08 n.d. 248 n.d n.d. 249 n.d n.d. 250 0.13 n.d. 251 4.4 n.d. 252 0.20n.d. 253 57.7 n.d. 254 0.27 n.d. 255 60.4 n.d. 256 0.28 n.d. 257 0.17n.d. 258 0.15 n.d. 259 0.15 n.d. 260 0.85 n.d. 261 0.63 n.d. 262 92.7n.d. 263 0.2 n.d. 264 284.2 n.d. 265 0.18 n.d. 266 505.7 n.d. 267 1.18n.d. 268 1.16 n.d. 269 n.d. n.d. 270 n.d. n.d. 271 n.d. n.d. 272 n.d.n.d. 273 n.d. n.d. 274 n.d. n.d. 275 0.122 n.d. 276 2.813 n.d. 277 0.35n.d. 278 0.99 n.d. 279 17.244 n.d. 280 417.076 n.d. 281 0.081 n.d. 2820.1015 n.d. 283 76.542 n.d. 284 0.525 n.d. 285 0.19 n.d. 286 0.71 n.d.287 0.117 n.d. 288 51.102 n.d. 289 0.152 n.d. 290 0.252 n.d. 291 2.406n.d. 292 1.16 n.d. 293 0.253 n.d. 294 0.396 n.d. 295 0.318 n.d. 296 0.32n.d. 297 0.417 n.d. 298 10.194 n.d. 299 142.5 n.d. 300 5.926 n.d. 3010.243 n.d. 302 1.268 n.d. 303 0.352 n.d. 304 1.065 n.d. 305 0.313 n.d.306 0.204 n.d. 307 0.124 n.d. 308 125.333 n.d. 309 1.77 n.d. 310 3.224n.d. 311 0.631 n.d. 312 0.319 n.d. 313 0.371 n.d. 314 0.213 n.d. 31540.946 n.d. 316 0.107 n.d. 317 0.089 0.95  318 43.728 n.d. 319 0.414n.d. 320 0.81 n.d. 321 0.144 n.d. 322 0.161 n.d. 323 0.135 n.d. 32421.715 n.d. 325 0.059 n.d. 326 6.133 n.d. n.d. = not determined

There are also assays that could be used to demonstrate the effect ofthe compounds of this invention in a cellular context.

Cellular Proliferation Assay in SJSA-1 and SAOS-2 Cells Based onYO-PRO®-1 Iodide Staining

The effect of PPI (protein-protein interaction) inhibitors on cellgrowth of p53 wild-type or mutant cells is assessed in a proliferationassay based on YO-PRO®-1 iodide staining (J Immunol Methods. 1995;185(2):249-58). The principal of this assay is the use of theDNA-intercalating dye YO-PRO®-1 iodide which upon binding to DNA emits astrong fluorescence signal. In addition, the dye is membrane-impermeantand thus, apoptotic cells can be distinguished from the viable cellpopulation during the same assay. In the absence of cellpermeabilization, the dye is only entering into cells that are beginningto undergo apoptosis. After treatment of the cells with a lysis buffer,the total cell number can be estimated.

To test PPI inhibitors on cell growth, SJSA-1 cells (p53 wild-typecells) and SAOS-2 cells (p53 null cells) are plated out into 96-wellmicro-titer plates and treated with decreasing concentrations of thecompounds. After a 72 hour incubation period, 2.5 μM YO-PRO®-1 iodide isdirectly added to the cells and a first read-out is performed using astandard fluorescence plate reader (filter setting 485/530 nm) revealingthe relative number of apoptotic cells. Subsequently, cells arepermeabilized by directly adding lysis buffer containing the detergentNP40, EDTA and EGTA to obtain final concentrations of 0.01% and 5 mM,respectively. After complete permeabilization, the total cell number isquantified during a second read using the fluorescence plate reader withthe same settings.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material. Compounds of the invention and intermediatescan also be converted into each other according to methods generallyknown to those skilled in the art.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

In Vivo Experiments

There are also experiments that can demonstrate the antitumor activityof compounds of the formula (I) in vivo.

For example, female Harlan (Indianapolis, Ind., USA) athymic nu/nu micewith s.c. transplanted human osteosarcoma SJSA-1 tumors can be used todetermine the anti-tumor activity of p53/MDM2 interaction inhibitors. Onday 0, with the animals under peroral Forene®(1-chloro-2,2,2-trifluoroethyldifluormethylether, Abbot, Wiesbaden,Germany) narcosis, 3×10⁶ cells are injected under the skin on theanimals' left flank. When tumors reach a volume of 100 mm³, the mice aredivided at random into groups of 6-8 animals and treatment commences.The treatment is carried out for a 2-3 weeks period with peroral,intravenous or intra-peritoneal administration twice daily (or lessfrequently) of a compound of the formula (I) in a suitable vehicle atdefined doses. The tumors are measured twice a week with a slide gaugeand the volume of the tumors is calculated. As an alternative to cellline SJSA-1, other cell lines may also be used in the same manner, forexample,

-   -   the HCT116 colon carcinoma cell line (ATCC No. CCL-247);    -   the LNCaP clone FGC prostate carcinoma cell line (ATCC No.        CRL-1740);    -   the RKO colon carcinoma cell line (ATCC No. CRL-2577);    -   the HT1080 fibrosarcoma cell line (ATCC No. CCL-121);    -   the A375 malignant melanoma cell line (ATCC No. CRL-1619),    -   the NCI-H460 large cell lung carcinoma cell line (ATCC No.        HTB-177);    -   the JEG-3 choriocarcinoma (ATCC No. HTB-36)    -   the ZR-75-1 breast ductal carcinoma (ATCC No. CRL-1500)

What is claimed is:
 1. The crystalline form A of4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile,characterized by a x-ray powder diffraction pattern comprising 4 or more2 theta values selected from the group consisting of 6.54±0.2,14.29±0.2, 15.72±0.2, 16.78±0.2, 17.82±0.2, 19.41±0.2, 20.10±0.2°,20.67±0.2, 23.65±0.2 and 25.82±0.2, at a temperature of about 22° C., inparticular 16.78±0.2, 19.41±0.2, 23.65±0.2 and 25.82±0.2.
 2. Thecrystalline form A of4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile,characterized by a x-ray powder diffraction pattern comprising 4 or more2 theta values selected from the group consisting of 6.25±0.2,10.34±0.2, 14.83±0.2, 15.33±0.2, 15.84±0.2, 19.16±0.2, 19.50±0.2°,20.94±0.2, 22.32±0.2, 25.05±0.2 and 25.74±0.2, at a temperature of about22° C.
 3. The crystalline form A (ethanol solvate) of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one,characterized by a x-ray powder diffraction pattern comprising 4 or more2 theta values selected from the group consisting of 9.89±0.2,12.33±0.2, 14.61±0.2, 16.21±0.2, 16.66±0.2, 17.50±0.2, 17.78±0.2,19.83±0.2, 20.56±0.2, 22.35±0.2, 22.98±0.2° at a temperature of about22° C.
 4. The crystalline form B (succinic acid co-crystal) of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one,characterized by a x-ray powder diffraction patter comprising 4 or more2 theta values selected from the group consisting of 9.04±0.2,17.27±0.2, 19.52±0.2, 20.85±0.2, 21.14±0.2, 23.42±0.2, 23.67±0.2,24.54±0.2, 26.95±0.2° at a temperature of about 22° C.
 5. Thecrystalline form C (hydrate) of(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one,characterized by a x-ray powder diffraction pattern comprising 4 or more2 theta values selected from the group consisting of 10.09±0.2,14.52±0.2, 14.88±0.2, 16.93±0.2, 17.56±0.2, 19.18±0.2, 20.46±0.2,20.87±0.2, 21.86±0.2, 25.00±0.2 25.68±0.2, 28.57±0.2, 32.17±0.2° at atemperature of about 22° C.
 6. The crystalline form A of(S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one,characterized by a x-ray powder diffraction pattern comprising 4 or more2 theta values selected from the group consisting of 9.98±0.2,12.56±0.2, 14.58±0.2, 14.95±0.2, 15.55±0.2, 17.08±0.2, 17.44±0.2,19.72±0.2, 23.83±0.2, 25.78±0.2, 26.26±0.2° at a temperature of about22° C., in particular 14.58±0.2, 17.08±0.2 and 17.44±0.2.
 7. A methodfor the treatment of a disorder or a disease mediated by the activity ofMDM2 and/or MDM4 comprising the step of administering to a subject atherapeutically effective amount of a compound selected from:(S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile;(S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one;(S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one;and(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one.